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Cited by 527Nanoparticle-Based Drug DeliveryAdvanced Drug Delivery SystemsPharmacology and Nanomedicine Research

Nanotechnology approaches for global infectious diseases

Kirtane, Ameya R., Verma, Malvika, Karandikar, Paramesh, Furin, Jennifer, Langer, Robert, Traverso, Giovanni·2021·Nature Nanotechnology
DOI 10.1038/s41565-021-00866-8
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Abstract

Infectious diseases are a major driver of morbidity and mortality globally. Treatment of malaria, tuberculosis and human immunodeficiency virus infection are particularly challenging, as indicated by the ongoing transmission and high mortality associated with these diseases. The formulation of new and existing drugs in nano-sized carriers promises to overcome several challenges associated with the treatment of these diseases, including low on-target bioavailability, sub-therapeutic drug accumulation in microbial sanctuaries and reservoirs, and low patient adherence due to drug-related toxicities and extended therapeutic regimens. Further, nanocarriers can be used for formulating vaccines, which represent a major weapon in our fight against infectious diseases. Here we review the current burden of infectious diseases with a focus on major drivers of morbidity and mortality. We then highlight how nanotechnology could aid in improving existing treatment modalities. We summarize our progress so far and outline potential future directions to maximize the impact of nanotechnology on the global population.

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Written from the paper’s full text.

TL;DR

This review argues that nanocarriers can improve treatment of global infectious diseases by enabling sustained, local, targeted, and resistance-overcoming drug delivery, with the most clinically advanced examples in HIV and promising preclinical work in TB and malaria. It also highlights mRNA/lipid nanoparticle vaccines for SARS-CoV-2 and outlines cost, manufacturing, regulatory, and patient-acceptance barriers to translation.

Key findings

Long-acting injectable antiretroviral nanosuspensions are the most clinically advanced nanotechnology in HIV: cabotegravir and rilpivirine nanosuspensions (mean diameter 200 nm) had estimated half-lives of 25–54 days and 44–61 days, respectively, enabling dosing every 1–3 months, and in Phase IIb trials the combination suppressed disease equivalently to oral tablets. Preclinical nanomedicines improved anti-infective exposure and efficacy: pulmonary itraconazole nanoparticles gave tenfold higher lung drug concentrations than oral Sporanox, liposomal ciprofloxacin doubled lung half-life (~3 h versus ~1.5 h) and produced no deaths in a *Francisella tularensis* model versus all untreated/free-drug mice dying within 14 days, and imipenem-loaded poly(caprolactone) nanoparticles reduced MICs 250-fold and 62.5-fold versus free imipenem in resistant *K. pneumoniae* and *P. aeruginosa*. In TB, oral solid lipid nanoparticles produced no detectable tubercle bacilli after five doses given every tenth day, whereas 46 daily doses of free drugs were required for the same benefit. mRNA-based vaccines using lipid nanocarriers showed >90% efficacy against SARS-CoV-2, illustrating the translational impact of nanotechnology.

Methods

Narrative review of nanotechnology approaches for global infectious diseases, with a stated focus on HIV, TB, and malaria and additional discussion of SARS-CoV-2 mRNA/protein vaccines. Evidence base consists of published preclinical and clinical studies, including rodent and non-human primate models, clinical trials, and examples from clinicaltrials.gov; no systematic search strategy, inclusion criteria, or meta-analysis is reported. Main analysis is a qualitative synthesis of selected examples across sustained systemic delivery, local delivery, targeted delivery, resistance overcoming, and advanced preclinical/clinical technologies.

Limitations

The paper states that translation is limited by cost, synthesis/storage conditions in low-resource settings, reproducibility and bulk production, regulatory differences across authorities, and patient acceptability; it also notes that enhanced nanocarrier permeability and infection-site targeting are not clearly established in humans, may correlate with infection severity, and often rely on intravenous administration that may be impractical in resource-limited or mass-drug-administration settings. For long-acting injectables, the paper states limitations including need for caregiver administration, common injection-site reactions, refrigeration requirements for rilpivirine, no mechanism to withdraw drug exposure after injection, and restriction to drugs with daily oral doses below 25–50 mg. Evident from the text: as a narrative review, the evidence is selectively presented rather than systematically synthesized, many cited examples remain preclinical or rodent-based, and no quantitative pooled effect estimates are provided.

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Integrity signals

Registry

Crossref · 10.1038/s41565-021-00866-8

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation
    § Nanotechnology in treating IDs · p. 1

    HIV-infected individuals require lifelong treatment to ensure control of the viral burden.

    “HIV-infected individuals require lifelong treatment to ensure control of the viral burden 10 .”
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    • cites [10] Kirtane, A. R., Langer, R. & Traverso, G. Past, present, and future drug delivery systems for antiretrovirals. J. Pharm. Sci. 105, 3471–3482 (2016). source

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    § Nanotechnology approaches for global infectious diseases · p. 1

    Clinical trials for infectious diseases are lagging compared with conditions such as cancer and cardiovascular diseases.

    “Unfortunately, clinical trials for these infectious diseases (IDs) are also lagging compared with conditions such as cancer and cardiovascular diseases (Fig. 1d) 1”
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    • cites [1] Roth, G. A. et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the global burden of disease Study 2017. Lancet 392, 1736–1788 (2018). source

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    § Nanotechnology in treating IDs · p. 1

    To treat TB, a combination of pills must be consumed over a period of several months to years-often multiple times a day.

    “To treat TB, a combination of pills must be consumed over a period of several months to years-often multiple times a day 11 .”
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    • cites [11] Treatment of Tuberculosis: Guidelines 4th edn (WHO, 2010); https://www.who.int/tb/publications/2010/9789241547833/en/

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    § Nanotechnology approaches for global infectious diseases · p. 1

    Lack of safe and effective drugs is central to our inability to treat infectious diseases.

    “The lack of safe and effective drugs is central to our inability to treat IDs 2 .”
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    • cites [2] Kinch, M. S., Patridge, E., Plummer, M. & Hoyer, D. An analysis of FDA-approved drugs for infectious disease: antibacterial agents. Drug Discov. Today 19, 1283–1287 (2014). source

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    § Nanotechnology in treating IDs · p. 1

    Prolonged and complicated dosing regimens with high pill burden result in lower patient adherence and, ultimately, failure of treatment.

    “Prolonged and complicated dosing regimens with high pill burden result in lower patient adherence and, ultimately, failure of treatment.”
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    § Nanotechnology approaches for global infectious diseases · p. 1

    Mortality rates are highest in developing countries, where resources such as vaccines and anti-infectives may be limited.

    “Mortality rates are highest in developing countries, where resources such as vaccines and anti-infectives may be limited (Fig. 1b) 1 .”
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    • cites [1] Roth, G. A. et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the global burden of disease Study 2017. Lancet 392, 1736–1788 (2018). source

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    § Nanotechnology approaches for global infectious diseases · p. 1

    Although the overall number of deaths is declining, the gap between deaths in high SDI countries and low SDI countries remains substantial.

    “Temporal trends in mortality show that although the overall number of deaths is declining, the gap between deaths in high socio-demographic index (SDI) countries and low SDI countries remains substantial (Fig. 1c) 1 .”
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    • cites [1] Roth, G. A. et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the global burden of disease Study 2017. Lancet 392, 1736–1788 (2018). source

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    § Nanotechnology approaches for global infectious diseases · p. 1

    In some cases, a lack of drug efficacy can be attributed to pathogen resistance, which then requires a more expensive drug regimen for cure.

    “In some cases, a lack of drug efficacy can be attributed to pathogen resistance, which then requires a more expensive drug regimen for cure 3 .”
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    • cites [3] Munita, J. M. & Arias, C. A. Mechanisms of antibiotic resistance. Microbiol. Spectrum 4, VMBF-0016-2015. (2016). source

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    § Nanotechnology approaches for global infectious diseases · p. 1

    Nanotechnology has the potential to transform both detection and treatment of a wide range of diseases.

    “Nanotechnology has the potential to transform both detection and treatment of a wide range of diseases.”
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    § Nanotechnology approaches for global infectious diseases · p. 1

    Poor patient adherence to therapies and the need for sustained patient monitoring are major obstacles to effective treatment.

    “Poor patient adherence to therapies and the need for sustained patient monitoring are major obstacles to effective treatment 4 .”
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    • cites [4] Sabaté, E. Adherence to Long-Term Therapy: Evidence for Action (WHO, 2003).

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    § Nanotechnology approaches for global infectious diseases · p. 1

    High mortality rates are associated with lower respiratory infections, diarrhoea, tuberculosis, HIV infection and malaria.

    “High mortality rates are associated with lower respiratory infections, diarrhoea, tuberculosis (TB), human immunodeficiency virus (HIV) infection and malaria (Fig. 1a) 1 .”
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    • cites [1] Roth, G. A. et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the global burden of disease Study 2017. Lancet 392, 1736–1788 (2018). source

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    § Nanotechnology approaches for global infectious diseases · p. 1

    Infectious diseases are a major driver of morbidity and mortality globally.

    “Infectious diseases are a major driver of morbidity and mortality globally.”
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    • cites [1] Roth, G. A. et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the global burden of disease Study 2017. Lancet 392, 1736–1788 (2018). source

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    § Nanotechnology approaches for global infectious diseases · p. 1

    Poor procurement practices, the inability to pay for drugs and poor stability of drug products at high temperature and humidity prevent access to effective treatments.

    “Poor procurement practices, the inability to pay for drugs and poor stability of drug products at high temperature and humidity prevent access to effective treatments 5 .”
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    • cites [5] Pheage, T. Dying from Lack of Medicines (United Nations, 2016); https://www.un.org/africarenewal/magazine/december-2016-march-2017/dying-lack-medicines source

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    § Nanotechnology approaches for global infectious diseases · p. 1

    Nanosystems have been the subject of intensive research over the past few decades, resulting in FDA-approved chemotherapeutics, anaesthetics, imaging agents, nutritional supplements and others.

    “Nanosystems have been the subject of intensive research over the past few decades, resulting in Food and Drug Administration (FDA)-approved chemotherapeutics, anaesthetics, imaging agents, nutritional supplements and others 6 .”
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    • cites [6] Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic. Bioeng. Transl. Med. 1, 10–29 (2016). source

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    § Nanotechnology in treating IDs · p. 3

    In that study, the highest tissue uptake was achieved with PEG-coated nanoparticles; however, tissue uptake was limited to the lower reproductive tract.

    “The highest tissue uptake was achieved with PEG-coated nanoparticles; however, tissue uptake was limited to the lower reproductive tract.”
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    • cites [23] Cu, Y., Booth, C. J. & Saltzman, W. M. In vivo distribution of surface-modified PLGA nanoparticles following intravaginal delivery. J. Control. Release 156, 258–264 (2011). source

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    § Nanotechnology in treating IDs · p. 2

    A drawback of some polymeric and liposomal formulations is that they require large quantities of excipients to control drug release, which increases the size of the injection and limits the amount of drug that can be administered.

    “A drawback of some polymeric and liposomal formulations is that they require large quantities of excipients to control drug release. This increases the size of the injection and limits the amount of drug that can be administered.”
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    § Nanotechnology in treating IDs · p. 3

    Cunha-Reis et al. demonstrated that nanoparticles loaded with efavirenz and embedded in a water-soluble film showed lower leakage and enabled higher tissue concentrations than nanoparticle dispersions.

    “Cunha-Reis et al. demonstrated that nanoparticles loaded with an anti-HIV drug (efavirenz) and embedded in a water-soluble film showed lower leakage and enabled higher tissue concentrations than nanoparticle dispersions 25 .”
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    • cites [25] Cunha-Reis, C. et al. Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs. J. Control. Release 243, 43–53 (2016). source

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    § Nanotechnology in treating IDs · p. 2

    In a rat model, intravenously administered MiKasomes distributed to several tissues, where they released drug gradually resulting in an eightfold increase in drug half-life.

    “In a rat model, intravenously administered Mikasomes distributed to several tissues, where they released drug gradually resulting in an eightfold increase in drug half-life.”
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    • cites [14] Fielding, R. M., Lewis, R. O. & Moon-McDermott, L. Altered tissue distribution and elimination of amikacin encapsulated in unilamellar, low-clearance liposomes (MiKasome). Pharm. Res. 15, 1775–1781 (1998). source

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    § Nanotechnology in treating IDs · p. 3

    Acyclovir monophosphate nanoparticles protected ~54% of mice infected with HSV-2 30 min post-treatment, whereas soluble drug protected only 16%.

    “Acyclovir monophosphate nanoparticles protected ~54% of the mice that were infected with HSV-2 30 min post-treatment. In contrast, the soluble drug protected only 16% of the mice from viral challenge.”
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    • cites [26] Ensign, L. M. et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci. Transl. Med. 4, 138ra79 (2012). source

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    § Nanotechnology in treating IDs · p. 3

    Nanocarriers can be engineered to release drugs in the presence of certain triggers and provide temporal control on drug exposure.

    “Nanocarriers can be engineered to release drugs in the presence of certain triggers and provide temporal control on drug exposure.”
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    § Nanotechnology in treating IDs · p. 3

    Encapsulation of drugs in nanocarriers allows for sustained drug delivery, thereby reducing dosing frequency.

    “Encapsulation of drugs in nanocarriers allows for sustained drug delivery, thereby reducing dosing frequency.”
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    § Nanotechnology in treating IDs · p. 2

    Drug release from polyester-based systems occurs via bulk degradation of the polymer and drug diffusion and can be modified by altering the hydrophobicity of the monomer, polymer chain length and particle size.

    “Drug release occurs via bulk degradation of the polymer and drug diffusion 12 and can be modified by altering the hydrophobicity of the monomer, polymer chain length and particle size 13 .”
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    • cites [12] Langer, R. Drug delivery and targeting. Nature 392, 5–10 (1998).

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    • cites [13] Makadia, H. K. & Siegel, S. J. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 3, 1377–1397 (2011). source

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    § Nanotechnology in treating IDs · p. 3

    Nanocarriers may enhance drug uptake in cells and improve efficacy against intracellular pathogens.

    “Nanocarriers may enhance drug uptake in cells and improve efficacy against intracellular pathogens.”
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    § Nanotechnology in treating IDs · p. 2

    An important consideration with sustained release systems is the potential for prolonged exposure to sub-therapeutic concentrations, which may lead to drug resistance.

    “An important consideration with sustained release systems is the potential for prolonged exposure to sub-therapeutic concentrations, which may lead to drug resistance 19 .”
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    • cites [19] Wistrand-Yuen, E. et al. Evolution of high-level resistance during low-level antibiotic exposure. Nat. Commun. 9, 1599 (2018). source

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    § Nanotechnology in treating IDs · p. 4

    Compared with healthy mice, transfection efficiency of polyplex in mice treated with lipopolysaccharide was reduced by about tenfold, and pre-treatment with N-acetyl cysteine restored transfection efficiency.

    “Compared with healthy mice, the transfection efficiency of the polyplex in mice treated with lipopolysaccharide was reduced by about tenfold. Impressively, pre-treatment with N -acetyl cysteine restored transfection efficiency in the inflammation model.”
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    • cites [36] Suk, J. S. et al. N-acetylcysteine enhances cystic fibrosis sputum penetration and airway gene transfer by highly compacted DNA nanoparticles. Mol. Ther. 19, 1981–1989 (2011). source

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    § Nanotechnology in treating IDs · p. 4

    The scaffold did enable slow release of silver; however, toxicity to host cells was not reduced.

    “The scaffold did enable the slow release of silver; however, toxicity to host cells was not reduced 40 .”
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    • cites [40] Mohiti-Asli, M., Pourdeyhimi, B. & Loboa, E. G. Skin tissue engineering for the infected wound site: biodegradable PLA nanofibers and a novel approach for silver ion release evaluated in a 3D coculture system of keratinocytes and Staphylococcus aureus. Tissue Eng. Pt C 20, 790–797 (2014). source

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    Interpretationcitation
    § Nanotechnology in treating IDs · p. 4

    These results suggest that the presence of biofilms plays a role in chronic infections and non-healing wounds, and strategies that overcome biofilm resistance may help treat these infections.

    “These results suggest that the presence of biofilms plays a role in chronic infections and non-healing wounds, and strategies that overcome biofilm resistance may help treat these infections.”
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    § Nanotechnology in treating IDs · p. 3

    PLGA nanoparticles containing cationic spermidine have been used for siRNA-based knockdown of the same target, and have shown better protection than lipofectamine lipoplexes.

    “Interestingly, PLGA nanoparticles containing cationic spermidine have been used for siRNA-based knockdown of the same target, and have shown better protection than lipofectamine lipoplexes 28 .”
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    • cites [28] Steinbach, J. M., Weller, C. E., Booth, C. J. & Saltzman, W. M. Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection. J. Control. Release 162, 102–110 (2012). source

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    § Nanotechnology in treating IDs · p. 3

    PLGA nanoparticles had similar knockdown efficiency to lipoplexes, but elicited lower inflammation.

    “The authors found that the PLGA nanoparticles had a similar knockdown efficiency to lipoplexes, but elicited lower inflammation (as observed by measuring neutrophil invasion using immunohistochemistry).”
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    • cites [28] Steinbach, J. M., Weller, C. E., Booth, C. J. & Saltzman, W. M. Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection. J. Control. Release 162, 102–110 (2012). source

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    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Aminoglycosides largely accumulate in the lysosomes and are likely to be ineffective against cytosolic pathogens.

    “aminoglycosides largely accumulate in the lysosomes and are likely to be ineffective against cytosolic pathogens 64 .”
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    • cites [64] Tulkens, P. & Trouet, A. The uptake and intracellular accumulation of aminoglycoside antibiotics in lysosomes of cultured rat fibroblasts. Biochem. Pharmacol. 27, 415–424 (1978). source

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    § Nanotechnology in treating IDs · p. 5

    In rats, 60% of the drug dose was found in the RES organs 8 h after treatment with nanoparticles, whereas only 12% was recovered in the RES tissues after soluble drug alone.

    “In rats, 60% of the drug dose was found in the RES organs 8 h after treatment with nanoparticles. In contrast, after treatment with the soluble drug alone, only 12% of the drug was recovered in the RES tissues.”
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    • cites [44] Löbenberg, R., Araujo, L., von Briesen, H., Rodgers, E. & Kreuter, J. Body distribution of azidothymidine bound to hexyl-cyanoacrylate nanoparticles after i.v. injection to rats. J. Control. Release 50, 21–30 (1998). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Encapsulation in nanocarriers offers opportunities to increase cell uptake of anti-infectives and alter their intracellular disposition.

    “Encapsulation in nanocarriers offers opportunities to increase cell uptake of anti-infectives and alter their intracellular disposition (Fig. 4b).”
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    § Review Article | FOCUS Review Article | FOCUS · p. 6

    Nanoparticle-based treatment with pentamidine encapsulated in PLGA nanoparticles functionalized with a nanobody enabled a tenfold dose reduction in vivo.

    “Nanoparticle-based treatment enabled a tenfold dose reduction in vivo.”
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    • cites [55] Arias, J. L. et al. Nanobody conjugated PLGA nanoparticles for active targeting of African trypanosomiasis. J. Control. Release 197, 190–198 (2015). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Resistance results from the secretion of drug-inactivating enzymes and/or the pathogens switching to a state of reduced metabolic activity, forming biofilms, adopting an intracellular life cycle or being obligate intracellular pathogens.

    “Resistance results from the secretion of drug-inactivating enzymes and/or the pathogens switching to a state of reduced metabolic activity, forming biofilms, adopting an intracellular life cycle or being obligate intracellular pathogens 3 .”
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    • cites [3] Munita, J. M. & Arias, C. A. Mechanisms of antibiotic resistance. Microbiol. Spectrum 4, VMBF-0016-2015. (2016). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    InvA497-functionalized gentamycin-loaded liposomes caused a 30% reduction in bacterial load in an in vitro model of Y. pseudotuberculosis infection, whereas albumin-functionalized liposomes had no effect.

    “InvA497-funtionalized gentamycin-loaded liposomes caused a 30% reduction in bacterial load in an in vitro model of Y. pseudotuberculosis infection, whereas albumin-functionalized liposomes had no effect 68 .”
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    • cites [68] Labouta, H. I. et al. Bacteriomimetic invasin-functionalized nanocarriers for intracellular delivery. J. Control. Release 220, 414–424 (2015). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Animals treated with mRNA nanoparticles produced antibody-based and CD8+ T-cell immune responses, and were completely protected from lethal challenges of Ebola virus, H1N1 influenza and Toxoplasma gondii.

    “Animals treated with mRNA nanoparticles produced antibody-based and CD8 + T-cell immune responses, and were completely protected from lethal challenges of Ebola virus, H1N1 influenza and Toxoplasma gondii .”
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    • cites [75] Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E4133–E4142 (2016). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Nanoparticles formed from penicillin G-squalene conjugate were rapidly taken up by cells and released drug in the endolysosomes, resulting in improved activity over the free drug.

    “Nanoparticles formed from this conjugate were rapidly taken up by cells and released drug in the endolysosomes. This resulted in improved activity over the free drug.”
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    • cites [67] Sémiramoth, N. et al. Self-assembled squalenoylated penicillin bioconjugates: an original approach for the treatment of intracellular infections. ACS Nano 6, 3820–3831 (2012). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Nanocarriers aid in the transport of mRNA across the cell membrane, enable endolysosomal escape and release the nucleic acid in the cytoplasm.

    “A key feature of nanocarriers is that they aid in the transport of mRNA across the cell membrane, enable endolysosomal escape and release the nucleic acid in the cytoplasm 74 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA Delivery. Mol. Ther. 27, 710–728 (2019). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Lipid-nanoparticle-formulated mRNA vaccines against H10N8 and H7N9 influenza viruses and SARS-CoV-2 are well tolerated and produce a robust humoral response.

    “Initial results with lipid-nanoparticle-formulated mRNA vaccines against H10N8 and H7N9 influenza viruses and SARS-CoV-2 indicate that these vaccines are well tolerated and that they produce a robust humoral response 76,77 .”
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    • cites [76] Jackson, L. A. et al. An mRNA vccine against SARS-CoV-2—preliminary report. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2022483 (2020). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Encapsulation of RNA in lipid carriers and their utility in vaccination was demonstrated.

    “encapsulation of RNA in lipid carriers 72 , and their utility in vaccination 73 , was demonstrated.”
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    • cites [72] Ostro, M. J., Giacomoni, D. & Dray, S. Incorporation of high molecular weight RNA into large artificial lipid vesicles. Biochem. Biophys. Res. Commun. 76, 836–842 (1977). source

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    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Surface functionalization with InvA497 is beneficial for enhancing both in vitro cell uptake and antimicrobial efficacy of polymeric nanoparticles.

    “This group has shown that surface functionalization with InvA497 is beneficial for enhancing both in vitro cell uptake and antimicrobial efficacy of polymeric nanoparticles 69 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Castoldi, A. et al. Aspherical and spherical InvA497-functionalized nanocarriers for intracellular delivery of anti-infective agents. Pharm. Res. 36, 22 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 7

    Nanoparticles can prevent, disrupt and inhibit or disperse bacteria from biofilm infections.

    “Nanoparticles can prevent, disrupt and inhibit or disperse bacteria from biofilm infections 30 (Fig. 4c).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Han, C. et al. Recent developments in the use of nanoparticles for treatment of biofilms. Nanotechnol. Rev. 6, 383–404 (2017). source

      Not checked in the free run.

    • Rests on an assumption: By forming a diffusion barrier, the extracellular polymeric matrix in the biofilm protects bacteria from high antibiotic concentrations, often leading to chronic infections.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 7

    In vitro studies revealed that antibiotics (azithromycin and rifampicin) were effective if applied immediately after infection, but not if applied after 24 or 48 h. However, encapsulation in nanoparticles partly restored their activities even when applied at 24 and 48 h after infection.

    “In vitro studies revealed that antibiotics (azithromycin and rifampicin) were effective if applied immediately after infection, but not if applied after 24 or 48 h. However, encapsulation in nanoparticles partly restored their activities even when applied at 24 and 48 h after infection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Toti, U. S. et al. Targeted delivery of antibiotics to intracellular chlamydial infections using PLGA nanoparticles. Biomaterials 32, 6606–6613 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Nanotechnology has been most actively studied in the clinic and in large animals for the treatment and prevention of HIV infection; for malaria and TB, nanotechnology has been pursued with less gusto, mainly limited to preclinical trials in rodents.

    “nanotechnology has been most actively studied in the clinic and in large animals for the treatment and prevention of HIV infection (Table 1). In contrast, for malaria and TB, nanotechnology has been pursued with less gusto. For these IDs, work has mainly been limited to preclinical trials in rodents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 8

    Free imipenem had negligible effect when co-administered with carbapenemase, while the nanoparticles had comparable bactericidal effects regardless of whether carbapenemase had been co-administered.

    “The results demonstrated that while free imipenem had negligible effect when co-administered with the enzyme, the nanoparticles had comparable bactericidal effects regardless of whether carbapenemase had been co-administered.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Shaaban, M. I., Shaker, M. A. & Mady, F. M. Imipenem/cilastatin encapsulated polymeric nanoparticles for destroying carbapenem-resistant bacterial isolates. J. Nanobiotechnol. 15, 29 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Long-acting injectable nanoparticles reduce dosing frequency, which stands to improve patient adherence.

    “Long-acting injectable nanoparticles reduce dosing frequency, which stands to improve patient adherence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 8

    These enzymes, such as β-lactamases and aminoglycoside-modifying enzymes, are readily transferred through horizontal gene transfer and have been implicated in the pattern of increasing drug resistance.

    “These enzymes, such as β -lactamases and aminoglycoside-modifying enzymes, are readily transferred through horizontal gene transfer and have been implicated in the pattern of increasing drug resistance 3 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Munita, J. M. & Arias, C. A. Mechanisms of antibiotic resistance. Microbiol. Spectrum 4, VMBF-0016-2015. (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Review Article | FOCUS Review Article | FOCUS · p. 8

    Nanoparticles have been used to protect antibiotic agents from enzymatic degradation and resensitize resistant bacteria to their bactericidal effects.

    “Nanoparticles have been used to protect antibiotic agents from enzymatic degradation and resensitize resistant bacteria to their bactericidal effects (Fig. 4d).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Long-acting injectable antiretrovirals are the most clinically advanced nanotechnology in HIV treatment.

    “Long-acting injectable antiretrovirals are the most clinically advanced nanotechnology in HIV treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 8

    In the drug-resistant model, ten treatments at elevated doses produced complete survival, but only two treatments with substantially lower doses of the liposomal combination also produced 100% survival.

    “Ten treatments at these elevated doses produced complete survival in the drug-resistant model. However, only two treatments with substantially lower doses of the liposomal combination also produced 100% survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Schiffelers, R. M. et al. In vivo synergistic interaction of liposome-coencapsulated gentamicin and ceftazidime. J. Pharmacol. Exp. Ther. 298, 369–375 (2001).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 8

    In a rat unilateral lung infection model with drug-sensitive K. pneumoniae, ten doses of the soluble drug combination treatment resulted in complete survival, while only a single dose of the liposomal combination produced the same effect.

    “In the drug-sensitive model, ten doses of the soluble drug combination treatment resulted in complete survival. Impressively, only a single dose of the liposomal combination produced the same effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Schiffelers, R. M. et al. In vivo synergistic interaction of liposome-coencapsulated gentamicin and ceftazidime. J. Pharmacol. Exp. Ther. 298, 369–375 (2001).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Both rilpivirine and cabotegravir nanosuspensions were safe and devoid of major adverse effects.

    “Both nanosuspensions were safe and devoid of major adverse effects 88 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Swindells, S., Flexner, C., Fletcher, C. V. & Jacobson, J. M. The critical need for alternative antiretroviral formulations, and obstacles to their development. J. Infect. Dis. 204, 669–674 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 11

    Long-chain-triglyceride-based self-microemulsifying systems containing β-artemether were demonstrated to be safe and have a notable improvement in antimalarial activity in vivo compared with Larither.

    “Long-chain-triglyceride-based self-microemulsifying systems containing β -artemether were demonstrated to be safe and have a notable improvement in the antimalarial activity in vivo compared with Larither.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Mandawgade, S. D., Sharma, S., Pathak, S. & Patravale, V. B. Development of SMEDDS using natural lipophile: application to β-artemether delivery. Int. J. Pharm. 362, 179–183 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Advanced preclinical and clinical nanotechnologies · p. 11

    Nanoformulation of multiple combined drugs is an efficient method for designing innovative therapeutics and can prevent resistance of the malaria parasite.

    “Nanoformulation of multiple combined drugs is an efficient method for designing innovative therapeutics and can prevent resistance of the malaria parasite.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Estimated half-lives of rilpivirine and cabotegravir in nanosuspensions were 44-61 days and 25-54 days, respectively, enabling administration every 1-3 months.

    “Estimated half-lives of rilpivirine and cabotegravir in nanosuspensions were 44-61 days (ref. 91 ) and 25-54 days (ref. 91 ), respectively, enabling administration every 1-3 months.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Verloes, R. et al. Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers. HIV Med. 16, 477–484 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Oral antiretroviral nanoparticles have been developed for paediatric use, produced by a novel emulsion template freeze-drying approach, and loaded with lopinavir and efavirenz.

    “Oral antiretroviral nanoparticles have been developed for paediatric use with the intent to replace tablets (which are difficult to swallow) and alcohol-containing solutions (which contain harmful excipients). These nanoparticles are produced by a novel emulsion template freeze-drying approach and have been loaded with lopinavir and efavirenz 99 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Giardiello, M. et al. Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies. Nat. Commun. 7, 13184 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    Co-loaded nanostructured lipid carriers with artemether and lumefantrine resulted in greater clearance of parasites from infected mice and had a clear benefit over individual drug-loaded carriers in terms of survival period and parasitaemia progression.

    “researchers showed that the systems resulted in greater clearance of parasites from infected mice and had a clear benefit over individual drug-loaded carriers in terms of survival period and parasitaemia progression 114 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Parashar, D., Aditya, N. P. & Murthy, R. S. R. Development of artemether and lumefantrine co-loaded nanostructured lipid carriers: physicochemical characterization and in vivo antimalarial activity. Drug Deliv. 23, 123–129 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Malaria is mainly treated using chemotherapy, with artemisinin-based combination therapy being integral to curing the disease.

    “Malaria is mainly treated using chemotherapy, with artemisinin-based combination therapy being integral to curing the disease 102 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] World Malaria Report 2017 (WHO, 2017); http://www.who.int/malaria/publications/world-malaria-report-2017/report/en/

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Advanced preclinical and clinical nanotechnologies · p. 11

    These approaches, using oily vehicles to enhance solubilization in the gastrointestinal tract, improve drug bioavailability and patient adherence.

    “These approaches, using oily vehicles to enhance solubilization in the gastrointestinal tract, improve drug bioavailability and patient adherence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 10

    These functionalized liposomes preferentially adhere to surface proteins decorating infected RBCs and reduce the overall parasitaemia.

    “These functionalized liposomes preferentially adhere to surface proteins decorating infected RBCs and reduce the overall parasitaemia.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] Marques, J. et al. Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery. Nanomedicine13, 515–525 (2017). source

      Not checked in the free run.

    • cites [108] Urbán, P., Estelrich, J., Cortés, A. & Fernàndez-Busquets, X. A nanovector with complete discrimination for targeted delivery to Plasmodium falciparum-infected versus non-infected red blood cells in vitro. J. Control. Release 151, 202–211 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Killing parasites in RBCs requires prolonged treatment with high doses, which results in toxicities, potential for missed doses and development of resistance.

    “Killing parasites in the RBCs requires prolonged treatment with high doses, which results in toxicities, potential for missed doses and development of resistance 104 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Baird, J. K. Effectiveness of antimalarial drugs. N. Engl. J. Med. 352, 1565–1577 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 10

    Blood stage parasites are the main therapeutic target, and researchers are developing various approaches to target antimalarials to infected RBCs.

    “Given that blood stage parasites are the main therapeutic target, researchers are developing various approaches to target antimalarials to infected RBCs 105-107 , thereby maximizing their therapeutic window.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [105] Marques, J. et al. Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery. Nanomedicine13, 515–525 (2017). source

      Not checked in the free run.

    • cites [106] Moles, E. et al. ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model. Biomaterials 145, 178–191 (2017). source

      Not checked in the free run.

    • cites [107] Urban, P. & Fernandez-Busquets, X. Nanomedicine against malaria. Curr. Med. Chem. 21, 605–629 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 9

    Lipid-based nanoparticles loaded with three to four antiretrovirals including lopinavir, ritonavir and tenofovir enhanced circulation times of the antiretrovirals and increased their uptake into mononuclear cells in peripheral blood and lymph nodes of macaques.

    “Nanoencapsulation enhanced circulation times of the antiretrovirals and increased their uptake into the mononuclear cells in peripheral blood and lymph nodes of macaques.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] Freeling, J. P., Koehn, J., Shu, C., Sun, J. & Ho, R. J. Y. Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates. AIDS Res. Hum. Retrov. 31, 107–114 (2015). source

      Not checked in the free run.

    • cites [96] Freeling, J. P., Koehn, J., Shu, C., Sun, J. & Ho, R. J. Y. Long-acting three-drug combination anti-HIV nanoparticles enhance drug exposure in primate plasma and cells within lymph nodes and blood. AIDS 28, 2625–2627 (2014). source

      Not checked in the free run.

    • Rests on an assumption: HIV persists in macrophages for prolonged durations, even in patients receiving antiretroviral therapy.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 10

    Liposomal drug delivery is an established platform with proven biocompatibility, but the oral route of administration is typically not used due to instability in the gastrointestinal tract.

    “Although liposomal drug delivery is an established platform with proven biocompatibility, the oral route of administration is typically not used due to instability in the gastrointestinal tract 109 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Allen, T. M. & Cullis, P. R. Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Deliv. Rev. 65, 36–48 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 9

    In rhesus macaques, prodrug nanoparticles maintained therapeutic concentrations of dolutegravir for ~40 days and extended the half-life of dolutegravir to ~19.5 days.

    “In rhesus macaques, prodrug nanoparticles maintained therapeutic concentrations of dolutegravir for ~40 days and extended the half-life of dolutegravir to ~19.5 days.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Mcmillan, J. et al. Pharmacokinetics of a long-acting nanoformulated dolutegravir prodrug in rhesus macaques. Antimicrob. Agents Chemother. 62, e01316-17 (2017). source

      Not checked in the free run.

    • cites [94] Sillman, B. et al. Creation of a long-acting nanoformulated dolutegravir. Nat. Commun. 9, 443 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Advanced preclinical and clinical nanotechnologies · p. 11

    NanoAbsorb is a solid microemulsion pre-concentrate formulation that can safely deliver artemether with higher antimalarial efficacy in vivo than the marketed formulation Larither.

    “NanoAbsorb is a solid microemulsion pre-concentrate formulation that can safely deliver the widely used drug artemether with higher antimalarial efficacy in vivo than the marketed formulation Larither 110 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Joshi, M., Pathak, S., Sharma, S. & Patravale, V. Solid microemulsion preconcentrate (NanOsorb) of artemether for effective treatment of malaria. Int. J. Pharm. 362, 172–178 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    RTS,S/AS01 (Mosquirix) is the only malaria vaccine candidate that has received a positive regulatory assessment, and it provides partial protection against malaria in young children.

    “There is only one malaria vaccine candidate that has received a positive regulatory assessment: RTS,S/AS01 (RTS,S) (Mosquirix), which is an injectable vaccine that provides partial protection against malaria in young children 115 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] RTS,S Clinical Trials Partnership. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367, 2284–2295 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    Researchers are attempting to improve the existing BCG vaccine and derive new vaccines to prevent TB.

    “Therefore, researchers are attempting to improve the existing BCG vaccine and derive new vaccines to prevent TB 133 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Kaufmann, S. H. E., Weiner, J. & von Reyn, C. F. Novel approaches to tuberculosis vaccine development. Int. J. Infect. Dis. 56, 263–267 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    In July 2015, European regulators approved the use of RTS,S, although it is at most 50% effective.

    “In July 2015, European regulators approved the use of the vaccine, although it is at most 50% effective 115 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] RTS,S Clinical Trials Partnership. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367, 2284–2295 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    Researchers have developed nebulized solid lipid particles and sodium alginate nanoparticles incorporating rifampicin, isoniazid and pyrazinamide to improve targeted bioavailability in the lungs and reduce hepatotoxicity.

    “Researchers have developed nebulized solid lipid particles 129 and sodium alginate nanoparticles 130 incorporating rifampicin, isoniazid and pyrazinamide to improve targeted bioavailability in the lungs and reduce hepatotoxicity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [129] Pandey, R. & Khuller, G. K. Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis. Tuberculosis 85, 227–234 (2005). source

      Not checked in the free run.

    • cites [130] Zahoor, A., Sharma, S. & Khuller, G. K. Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis. Int. J. Antimicrob. Agents 26, 298–303 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    BCG is the sole approved TB vaccine and offers only limited protection.

    “Bacillus Calmette-Guerin (BCG), which was introduced in 1921, is the sole approved TB vaccine, but it offers only limited protection 132 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Hawn, T. R. et al. Tuberculosis vaccines and prevention of infection. Microbiol. Mol. Biol. Rev. 78, 650–671 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    The antigen in RTS,S is formulated as virus-like particle and combined with a liposomal adjuvant system.

    “The antigen is formulated as virus-like particle and combined with a liposomal adjuvant system.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] RTS,S Clinical Trials Partnership. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367, 2284–2295 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    Unless radical action is taken, drug-resistant strains of M. tuberculosis will account for 25% of antimicrobial resistance-related deaths and cost the global economy US$16.7 trillion by the year 2050.

    “Unless radical action is taken, drug-resistant strains of M. tuberculosis will account for 25% of antimicrobial resistance-related deaths and cost the global economy US$16.7 trillion by the year 2050 119 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] O’Neill, J. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations (2016).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 13

    Most people with TB infection do not have symptoms, making it challenging for them to complete their regimens.

    “Given that most people with TB infection do not have symptoms, it can be challenging for them to complete their regimens 139 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Van Ginderdeuren, E., Bassett, J., Hanrahan, C., Mutunga, L. & Van Rie, A. Health system barriers to implementation of TB preventive strategies in South African primary care facilities. PLoS ONE 14, e0212035 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given
    § FOCUS | Review Article FOCUS | Review Article · p. 13

    Innovative and cost-effective nanotechnologies that take into consideration the challenges encountered in low SDI countries are most likely to benefit patients.

    “Innovative and cost-effective nanotechnologies that take into consideration the challenges that are encountered low SDI countries are most likely to benefit patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Challenges and outlook · p. 13

    In 2006, the International Centre for Technology Assessment and other consumer groups filed a legal petition against the FDA for perceived lack of initiative in regulating nanomaterial-containing products under their jurisdiction.

    “In 2006, the International Centre for Technology Assessment and other consumer groups filed a legal petition against the FDA for perceived lack of initiative in regulating nanomaterial-containing products under their jurisdiction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Nanotechnology: A Report of the US Food and Drug Administration Nanotechnology Task Force (USFDA, 2007).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 12

    TB is caused by the inhalation of droplet nuclei containing M. tuberculosis that enter the respiratory tract and infect the alveoli of the lungs.

    “TB is caused by the inhalation of droplet nuclei containing M. tuberculosis that enter the respiratory tract and infect the alveoli of the lungs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Pai, M. et al. Tuberculosis. Nat. Rev. Dis. Prim. 2, 16076 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Review Article | FOCUS Review Article | FOCUS · p. 13

    It is recommended that people with latent TB receive treatment to eradicate the mycobacteria and prevent progress to active disease.

    “It is also recommended that people who are infected with TB but do not have active disease (latent TB) receive treatment to eradicate the mycobacteria and prevent progress to active disease 138 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Latent Tuberculosis Infection: Updated and Consolidated Guidelines for Programmtic Management (WHO, 2018).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given
    § Challenges and outlook · p. 13

    The rapid translation of nanotechnologies from the bench to the people, and the impact that these systems have had on the SARS-CoV-2 pandemic, provide great promise.

    “Nonetheless, the rapid translation of nanotechnologies from the bench to the people, and the impact that these systems have had on the SARS-CoV-2 pandemic provide great promise.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § Challenges and outlook · p. 13

    The examples highlight many promising therapeutic strategies for developing nanomedicines to treat and prevent IDs.

    “The examples above highlight many promising therapeutic strategies for developing nanomedicines to treat and prevent IDs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Challenges and outlook · p. 13

    Nanotechnology is a multi-disciplinary field that requires intellectual property and commercialization strategies to grow.

    “Nanotechnology is a multi-disciplinary field that also requires intellectual property and commercialization strategies to grow 146 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Bhatia, P., Vasaikar, S. & Wali, A. A landscape of nanomedicine innovations in India. Nanotechnol. Rev. 7, 131–148 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § Challenges and outlook · p. 13

    To have maximum impact, nanotechnology solutions will need to overcome several financial, manufacturing and regulatory challenges.

    “However, to have the maximum impact, nanotechnology solutions will need to overcome several financial, manufacturing and regulatory challenges.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given
    § Conclusion · p. 13

    Simplifying the use of medicines and making drugs safer and more efficacious can improve patients' quality of life and reduce disease burden.

    “Simplifying the use of medicines and making drugs safer and more efficacious can improve patients' quality of life and reduce disease burden.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Challenges and outlook · p. 13

    The FDA created a Nano Task Force in response to the petition.

    “The FDA created a Nano Task Force in response 145 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Nanotechnology: A Report of the US Food and Drug Administration Nanotechnology Task Force (USFDA, 2007).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Review Article | FOCUS Review Article | FOCUS · p. 13

    Nanotechnology can potentially simplify dosing and minimize adverse events in the latent TB population, thereby greatly contributing to the elimination of TB.

    “Nanotechnology can potentially simplify dosing and minimize adverse events in this population, thereby greatly contributing to the elimination of TB.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Preventative TB regimens can last for 9 months and require multidrug therapy.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning
    § Challenges and outlook · p. 13

    Similar feats may be possible in treating other infectious diseases as well.

    “This example suggests that similar feats may be possible in treating other infectious diseases as well.”
    Quote in the paperNot a substantial claim
81 of 81

  • The paper relies on this without support.

    Nanocarriers are predominantly cleared by macrophages.

    “As nanocarriers are predominantly cleared by these cells (Fig. 3a), they have been widely used for targeting drugs to macrophages.”

  • The paper relies on this without support.

    Expression of certain targets/receptors in diseased areas may be elevated.

    “The expression of certain targets/receptors in diseased areas may be elevated.”

  • The paper relies on this without support.

    Drug molecules released while nanocarriers are in circulation are subject to non-selective distribution.

    “Drug molecules released while nanocarriers are in circulation are subject to non-selective distribution.”

  • The paper relies on this without support.

    Nanotechnology-based approaches have been the topic of intensive preclinical evaluation to improve the therapeutic index of ID drugs and simplify their use.

    “Nanotechnology-based approaches have been the topic of intensive preclinical evaluation to improve the therapeutic index of ID drugs and simplify their use.”

  • The paper relies on this without support.

    Nanoencapsulation may enhance drug accumulation at sites of infection.

    “Although nanoencapsulation may enhance drug accumulation at sites of infection”

  • The paper relies on this without support.

    Drug accumulation at sites of infection is increased in rodent models, but a substantial fraction of the drug is at off-target locations.

    “Although drug accumulation at sites of infection is increased in rodent models, a substantial fraction of the drug is at off-target locations.”

  • The paper relies on this without support.

    For triggered-release systems, some drug leakage is generally observed even in the absence of triggers.

    “For triggered-release systems, some drug leakage is generally observed even in the absence of triggers.”

  • The paper relies on this without support.

    The intravenous route of administration may not be practical in resource-limited settings or in mass drug administration campaigns.

    “the intravenous route of administration may not be practical in resource-limited settings or in mass drug administration campaigns.”

  • The paper relies on this without support.

    Both drug molecules and pathogens are unevenly distributed within host cells, and in the absence of colocalization, efficacy is compromised.

    “both drug molecules and pathogens are unevenly distributed within host cells, and in the absence of colocalization, efficacy is compromised”

  • The paper relies on this without support.

    By forming a diffusion barrier, the extracellular polymeric matrix in the biofilm protects bacteria from high antibiotic concentrations, often leading to chronic infections.

    “By forming a diffusion barrier, the extracellular polymeric matrix in the biofilm protects bacteria from high antibiotic concentrations, often leading to chronic infections.”

  • The paper relies on this without support.

    HIV persists in macrophages for prolonged durations, even in patients receiving antiretroviral therapy.

    “HIV persists in macrophages for prolonged durations, even in patients receiving antiretroviral therapy.”

  • The paper relies on this without support.

    Patients treated with injectable nanosuspensions are exposed to the drug for at least a month, and there is no mechanism to withdraw exposure in cases of adverse reactions.

    “Patients treated with injectable nanosuspensions are exposed to the drug for at least a month, and there is no mechanism to withdraw exposure in cases of adverse reactions.”

  • The paper relies on this without support.

    This problem has been addressed in clinical trials by providing patients with a lead-in period of oral drug therapy before the injection.

    “This problem has been addressed in clinical trials by providing patients with a lead-in period of oral drug therapy before the injection.”

  • The paper relies on this without support.

    In most clinical trials, the nanosuspensions have been administered by medical practitioners, and it is likely that patients will need to visit their caregiver for each injection.

    “in most clinical trials, the nanosuspensions have been administered by medical practitioners, and it is likely that patients will need to visit their caregiver for each injection.”

  • The paper relies on this without support.

    Artemether and lumefantrine are well accepted as a combination therapy for treating uncomplicated malaria, yet the current marketed formulation degrades in the gastrointestinal tract, leading to unpredictable pharmacokinetics.

    “Artemether and lumefantrine are well accepted as a combination therapy for treating uncomplicated malaria, yet the current marketed formulation degrades in the gastrointestinal tract, leading to unpredictable pharmacokinetics.”

  • The paper relies on this without support.

    There is a dearth of other new TB drugs in the pipeline.

    “and the dearth of others in the pipeline”

  • The paper relies on this without support.

    Preventative TB regimens can last for 9 months and require multidrug therapy.

    “These preventative regimens can last for 9 months and require multidrug therapy.”

  • The paper relies on this without support.

    Development of new drugs for global health solutions is expensive.

    “For global health solutions, development of new drugs is expensive.”

  • The paper relies on this without support.

    Excipients used in nanosystems, such as lyoprotectants, can increase the cost of many treatments.

    “Excipients used in nanosystems, such as lyoprotectants, can increase the cost of many treatments.”

  • The paper relies on this without support.

    Nanomedicines are likely to be three-dimensional constructs of multiple components with preferred spatial arrangements.

    “Nanomedicines are likely to be three-dimensional constructs of multiple components with preferred spatial arrangements.”
20 of 20

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure caption reverses what nanocarriers protect

    Minor

    Figure 4 says nanocarriers protect drug-degrading enzymes, whereas the accompanying text says they protect antibiotics from those enzymes.

  • Nitrous oxide and nitric oxide are conflated

    Minor

    The same polymeric-nanoparticle approach is described as releasing nitrous oxide and then as releasing nitric oxide. These are different compounds.

  • Cited daily-dosing trial is described as a nanosuspension trial

    Minor

    The paper attributes a Phase IIb result with rilpivirine and cabotegravir nanosuspensions to reference 93, but that reference's title describes cabotegravir plus rilpivirine given once a day. This contradicts the claimed formulation and dosing basis for the clinical result.

3 of 3

Cites

1 retracted

Flagged first, then by citations

2 of the 141 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Jain, R. et al. in Handbook of Nanomaterials for Industrial Applications Ch. 33 (Elsevier, 2018).

Cited by

Sorted by citations

Related

Authors
Kirtane, A. R., Verma, M., Karandikar, P., Furin, J., Langer, R., & Traverso, G.
Affiliations
  • Brigham and Women's Hospital (US)
  • Koch Institute for Integrative Cancer Research At MIT (US)
  • Harvard University (US)
ORCID
Venue
Nature Nanotechnology
Publisher
Springer Science and Business Media LLC
Published
2021-03-22
Volume
16
Issue
4
Pages
369-384
ISSN
  • 1748-3387 (ISSN-L)
  • 1748-3395
DOI
10.1038/s41565-021-00866-8
OpenAlex
W3139513515
Cited by
520
References
141
Citations by year
2026: 51 · 2025: 100 · 2024: 112 · 2023: 145 · 2022: 85 · 2021: 26 · 2020: 1
FWCI
6.35
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Nature Nanotechnology (publishedVersion)
  • PubMed (publishedVersion)
Funders
U.S. Department of Health & Human Services | National Institutes of Health (EB000244)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Pharmacology and Nanomedicine Research
Keywords
nanotechnology, infectious diseases, malaria, tuberculosis, HIV, nanocarriers, drug delivery, bioavailability, drug toxicity, patient adherence, nanovaccines, global health
MeSH terms
Communicable Diseases, Drug Carriers, Humans, Drug Delivery Systems, Nanotechnology, Nanoparticles

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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