Overcoming tumor microenvironment barriers: transformable and bioinspired nanomedicine strategies for deep tumor penetration

In the paper

“Earlier overviews have typically organized systems by material class or by a single trigger, but they seldom cross-compare how different design logics perform against specific tumor barriers or how deeply they penetrate in three-dimensional models and in vivo [16].”

What the sources say

• Check pendingcites [16] Carton F, Malatesta M. In vitro models of biological barriers for nanomedical research. Int J Mol Sci. 2022;23:8910. https://doi.org/10.3390/ijms23168910. source

In the paper

“In addition to imposing physical transport barriers, stromal cells can actively drive malignant progression and therapy resistance.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Pang LB, Li J, Zhang ZW, Zhang CQ. Lung cancer-associated mesenchymal stem cells mediate chemoresistance and malignant progression of lung cancer through activating HIF-1α. Eur Cell Mater. 2025;50:87–108. https://doi.org/10.22203/eCM.v050a06. source

In the paper

“In comparative terms, acid/GSH shrinkers emphasize interstitial passage and retention with relatively simple chemistries [22, 23], whereas protease-directed ultra-shrinkers are especially potent in desmoplastic matrices that overexpress MMPs, achieving deeper spread at the cost of more elaborate trigger design.”

What the sources say

• ?Not checked — no full text of the sourcecites [22] He Y, Fan X, Wu X, Hu T, Zhou F, Tan S, et al. pH-responsive size-shrinkable mesoporous silica-based nanocarriers for improving tumor penetration and therapeutic efficacy. Nanoscale. 2022;14:1271–84. https://doi.org/10.1039/d1nr07513f. source
• ?Not checked — no full text of the sourcecites [23] Ma X, Chen X, Yi Z, Deng Z, Su W, Chen G, et al. Size changeable nanomedicines assembled by noncovalent interactions of responsive small molecules for enhancing tumor therapy. ACS Applied Materials & Interfaces. 2022;14:26431–42. https://doi.org/10.1021/acsami.2c04698. source

In the paper

“Conversely, smaller particles (< 30 nm) diffuse more readily into deep tumor regions but are quickly cleared from circulation and may cause off-target effects [19].”

What the sources say

• Check pendingcites [19] Mellor RD, Uchegbu IF. Ultrasmall-in-nano: why size matters. Nanomaterials. 2022;12:2476. https://doi.org/10.3390/nano12142476. source

In the paper

“Interestingly, what appear to be barriers can also be exploited as triggers: local acidity and enzymatic activity can induce size shrinkage and charge reversal; hypoxia and redox gradients can open transcytotic pathways and expose latent ligands.”

What the sources say

• Check pendingcites [9] Nussbaum S, Shoukry M, Ashary MA, Kasbi AA, Baksh M, Gabriel E. Advanced tumor imaging approaches in human tumors. Cancers (Basel). 2022;14:1549. https://doi.org/10.3390/cancers14061549. source

In the paper

“Several nanomedicines, such as liposomal doxorubicin (DOX) and albumin-bound paclitaxel, have been approved for clinical use, with benefits primarily in reducing systemic toxicity.”

What the sources say

• Not checked yetcites [5] Liu B, Zhou H, Tan L, Siu KTH, Guan XY. Exploring treatment options in cancer: tumor treatment strategies. Signal Transduct Target Ther. 2024;9:175. https://doi.org/10.1038/s41392-024-01856-7. source

In the paper

“As a result, transformation kinetics and activation windows calibrated in protein-free buffers may differ markedly from those in plasma or interstitial fluid, underscoring the need to validate size- and charge-switching behavior under physiologically relevant protein concentrations [18].”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Yang H, Lu S, Wang S, Liu L, Zhu B, Yu S, et al. Evolution of the protein corona affects macrophage polarization. Int J Biol Macromol. 2021;191:192–200. https://doi.org/10.1016/j.ijbiomac.2021.09.081. source

In the paper

“For example, lung cancer-associated mesenchymal stem cells promote autophagy and epithelial-mesenchymal transition through HIF-1α-dependent signaling, thereby enhancing invasion and chemoresistance and underscoring that tumor-microenvironment remodeling is tightly coupled to drug response as well as penetration [8].”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Pang LB, Li J, Zhang ZW, Zhang CQ. Lung cancer-associated mesenchymal stem cells mediate chemoresistance and malignant progression of lung cancer through activating HIF-1α. Eur Cell Mater. 2025;50:87–108. https://doi.org/10.22203/eCM.v050a06. source

In the paper

“Systemically administered drugs are subject to rapid clearance, limited tumor accumulation, and most critically, poor tissue penetration.”

What the sources say

• Check pendingcites [2] Yun WS, Kim J, Lim DK, Kim DH, Jeon SI, Kim K. Recent studies and progress in the intratumoral administration of nano-sized drug delivery systems. Nanomaterials. 2023;13:2225. https://doi.org/10.3390/nano13152225. source
• Check pendingcites [3] Momoh J, Kapsokalyvas D, Vogt M, Hak S, Kiessling F, van Zandvoort M, et al. Intravital microscopy for real-time monitoring of drug delivery and nanobiological processes. Adv Drug Deliv Rev. 2022;189:114528. https://doi.org/10.1016/j.addr.2022.114528. source

In the paper

“Nanotechnology-based drug delivery systems offer new opportunities to improve pharmacokinetics, enable site-specific targeting, and enhance drug stability in circulation [4].”

What the sources say

• Check pendingcites [4] Tripathi D, Pandey P, Sharma S, Rai AK, Prabhu BHM. Advances in nanomaterials for precision drug delivery: insights into pharmacokinetics and toxicity. Bioimpacts. 2025;15:30573. https://doi.org/10.34172/bi.30573. source

In the paper

“Emerging patient-derived organoids (PDOs), co-culture spheroids and microfluidic tumor-on-a-chip platforms offer more faithful TME architectures and spatiotemporal gradients, and are thus particularly well suited for benchmarking “deep penetration” performance and validating model-informed design rules [11].”

What the sources say

• Check pendingcites [11] Wang E, Xiang K, Zhang Y, Wang XF. Patient-derived organoids (PDOs) and PDO-derived xenografts (PDOXs): new opportunities in establishing faithful pre-clinical cancer models. J Natl Cancer Cent. 2022;2:263–76. https://doi.org/10.1016/j.jncc.2022.10.001. source

In the paper

“Compared with normal tissues, tumors exhibit a constellation of abnormal features collectively referred to as the TME, including disorganized and hyperpermeable vasculature, dense extracellular matrix (ECM), elevated interstitial fluid pressure (IFP), aberrant enzyme expression, acidic pH, and hypoxic regions.”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Cabral H, Li J, Miyata K, Kataoka K. Controlling the biodistribution and clearance of nanomedicines. Nat Rev Bioeng. 2023;2:214–32. https://doi.org/10.1038/s44222-023-00138-1. source

In the paper

“Nanoparticles larger than 100 nm are more stable in circulation, with prolonged blood half-life, but face significant challenges in penetrating the dense ECM and IFP of tumors.”

What the sources say

• Check pendingcites [19] Mellor RD, Uchegbu IF. Ultrasmall-in-nano: why size matters. Nanomaterials. 2022;12:2476. https://doi.org/10.3390/nano12142476. source

In the paper

“In the same study, Cybulski et al. further demonstrated that positively charged AuNR(+) underwent complete charge inversion in serum-containing medium due to the adsorption of a predominantly anionic protein corona, which reduced close contact with cell membranes and limited penetration into inner spheroid layers [17].”

What the sources say

• Check pendingcites [17] Cybulski P, Bravo M, Chen JJ, Van Zundert I, Krzyzowska S, Taemaitree F, et al. Nanoparticle accumulation and penetration in 3D tumor models: the effect of size, shape, and surface charge. Front Cell Dev Biol. 2024;12:1520078. https://doi.org/10.3389/fcell.2024.1520078. source

In the paper

“They observed that larger nanospheres showed higher overall accumulation but shallower penetration, whereas smaller nanospheres and negatively charged particles could reach inner spheroid layers, and rod-shaped particles generally displayed more limited penetration than spherical ones [17].”

What the sources say

• Check pendingcites [17] Cybulski P, Bravo M, Chen JJ, Van Zundert I, Krzyzowska S, Taemaitree F, et al. Nanoparticle accumulation and penetration in 3D tumor models: the effect of size, shape, and surface charge. Front Cell Dev Biol. 2024;12:1520078. https://doi.org/10.3389/fcell.2024.1520078. source

In the paper

“Recent corona-focused analyses likewise emphasize that dynamic corona formation can substantially shift the zeta potential of nanoparticles and sterically shield pH- or redox-sensitive moieties [18].”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Yang H, Lu S, Wang S, Liu L, Zhu B, Yu S, et al. Evolution of the protein corona affects macrophage polarization. Int J Biol Macromol. 2021;191:192–200. https://doi.org/10.1016/j.ijbiomac.2021.09.081. source

In the paper

“Because activated fragments are often neutral to mildly negative, diffusion gains can outpace cellular entry, which encourages coupling shrinkage with a second lever such as latent cation exposure or ligand unmasking so that transport is not achieved at the expense of uptake [22, 24].”

What the sources say

• ?Not checked — no full text of the sourcecites [22] He Y, Fan X, Wu X, Hu T, Zhou F, Tan S, et al. pH-responsive size-shrinkable mesoporous silica-based nanocarriers for improving tumor penetration and therapeutic efficacy. Nanoscale. 2022;14:1271–84. https://doi.org/10.1039/d1nr07513f. source
• ?Not checked — no full text of the sourcecites [24] Ma T, Li W, Ye J, Huang C, Li Y, Qiu H, et al. GSH/pH dual response drug delivery system for photothermal enhanced gene-immunotherapy. Nanoscale. 2023;15:16947–58. https://doi.org/10.1039/d3nr03881e. source

In the paper

“Since charge reversal does not inherently reduce hydrodynamic size, diffusion through dense stroma can remain the bottleneck when activated diameters exceed about 50 nm; pairing partial downsizing with charge programming or introducing short, well-tolerated priming that preserves perfusion can mitigate this constraint [25].”

What the sources say

• ?Not checked — no full text of the sourcecites [25] Hu J, Zhou W, Zhou Y, Hu H, Ran S, Zhang Y. Ph-independent charge-reversal strategy for enhanced tumor penetration based on hyaluronidase-responsive tellurium-containing polycarbonate nanocarriers. J Mater Chem B. 2025;13:8483–95. https://doi.org/10.1039/d5tb00368g. source

In the paper

“In an MDA-MB-231 xenograft model, PRO achieved a TGI of 36.3% (vs PBS), whereas iPR reached 62.3% (5 μM) and 81.5% (8 μM) after 21 days (vs PBS), supporting a quantitatively stronger in vivo benefit than the parent PROTAC at matched/near-matched dosing.”

What the sources say

• ?Not checked — no full text of the sourcecites [81] He S, Fang Y, Wu M, Zhang P, Gao F, Hu H, et al. Enhanced tumor targeting and penetration of proteolysis-targeting chimeras through iRGD peptide conjugation: a strategy for precise protein degradation in breast cancer. J Med Chem. 2023;66:16828–42. https://doi.org/10.1021/acs.jmedchem.3c01539. source

In the paper

“In physiological urea they transitioned from Brownian diffusion (D ~ 0.03 μm2 s⁻1) to about 2.5 μm2 s⁻1, doubled cancer-cell uptake versus static PLT@Au, and in 4T1 tumors a single intratumoral dose plus 4 Gy γ-irradiation raised the sensitization enhancement rate to 1.89 (vs. 1.08 for passive PLT@Au), producing the largest 14-day tumor weight reduction without extra toxicity [63].”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Liu W, Nie H, Li H, Liu Y, Tian M, Wang S, et al. Engineered platelet cell motors for boosted cancer radiosensitization. J Colloid Interface Sci. 2024;658:540–52. https://doi.org/10.1016/j.jcis.2023.12.091. source

In the paper

“This process enhances adsorption-mediated transcytosis, allowing uniform penetration through 3.6 mm thick 2,3-Dimethylmaleic Anhydride (DMMA) xenografts and achieving potent tumor inhibition via mitochondrial cisplatin release with negligible systemic toxicity compared with the control groups [25].”

What the sources say

• ?Not checked — no full text of the sourcecites [25] Hu J, Zhou W, Zhou Y, Hu H, Ran S, Zhang Y. Ph-independent charge-reversal strategy for enhanced tumor penetration based on hyaluronidase-responsive tellurium-containing polycarbonate nanocarriers. J Mater Chem B. 2025;13:8483–95. https://doi.org/10.1039/d5tb00368g. source

In the paper

“Geometry engineering via high-curvature fusiform CaP (ENP5) lowers hydrodynamic drag, enabling long-range matrix traversal (over ~ 1.5 mm across the perivascular matrix in Huh-7 xenografts) enabling long-range matrix traversal and potent antitumor activity”

What the sources say

• Check pendingcites [51] Jiang X, Xu S, Miao Y, Huang K, Wang B, Ding B, et al. Curvature-mediated rapid extravasation and penetration of nanoparticles against interstitial fluid pressure for improved drug delivery. Proc Natl Acad Sci U S A. 2024;121:e2319880121. https://doi.org/10.1073/pnas.2319880121. source

In the paper

“Tat-A86 elastin-like polypeptide nanoparticles presented AP1 together with a CPP to form stable miRNA complexes, increasing 3D spheroid penetration and suppressing Lewis lung carcinoma (LLC) growth at equivalent doses [67].”

What the sources say

• Check pendingcites [67] Hong J, Sim D, Lee BH, Sarangthem V, Park RW. Multifunctional elastin-like polypeptide nanocarriers for efficient miRNA delivery in cancer therapy. J Nanobiotechnol. 2024;22:293. https://doi.org/10.1186/s12951-024-02559-5. source

In the paper

“iRGD conjugation to a BRD4 PROTAC via a GSH-responsive disulfide carbonate linker (iPR) improves solubility, enables αvβ3/NRP1-dependent uptake and CendR permeation, and strengthens BRD4 degradation and antitumor effects versus the parent small molecule [81].”

What the sources say

• ?Not checked — no full text of the sourcecites [81] He S, Fang Y, Wu M, Zhang P, Gao F, Hu H, et al. Enhanced tumor targeting and penetration of proteolysis-targeting chimeras through iRGD peptide conjugation: a strategy for precise protein degradation in breast cancer. J Med Chem. 2023;66:16828–42. https://doi.org/10.1021/acs.jmedchem.3c01539. source

In the paper

“Despite these hurdles, the strategic upside is compelling: cell-based and biomimetic systems can bypass endothelium and localize actively, and when augmented with CPP modules they achieve efficient cellular entry and endosomal escape to enable deep and uniform penetration.”

In the paper

“In orthotopic glioma they increased drug deposition nearly fivefold and extended median survival (median survival 38 days; vs PBS 18 days, EMV@GeNP 25 days, CatNbots 26 days, and NE@EDGNs 34 days) to 45 days without organ toxicity [64] (Fig. 4).”

What the sources say

• Check pendingcites [64] Gao Y, Mao M, Li Y, Xuan M, Wu Y, He Q. A self-directed trojanbot-enzymatic nanobot in neutrobot for active target therapy of glioblastoma. Nat Commun. 2025;16:5263. https://doi.org/10.1038/s41467-025-60422-z. source

In the paper

“Across integrin-, nucleolin-, and CXCR4-addressed designs, two shared effects dominate: (i) increased endothelial access and perivascular-to-interstitial spread (often via CendR/NRP1 pathways), and (ii) reinforced intracellular processing (e.g., PROTAC delivery or toxin activation) that converts deeper distribution into pharmacodynamic gain.”

In the paper

“Collagenase@CMSNs4.5 (DOX) | Collagen degradation on large-pore cationic mesoporous silica; enhanced doxorubicin delivery | Pancreatic tumor in vivo | Dense collagen-rich extracellular matrix | Tumor-slice depth profiling; detectable penetration depth: 1200 μm | Tumor inhibition rate 86% | [49]”

What the sources say

• ?Not checked — no full text of the sourcecites [49] Qiu N, Lv QY, Li CL, Song X, Wang YQ, Chen J, et al. Optimization and mechanisms of proteolytic enzyme immobilization onto large-pore mesoporous silica nanoparticles: enhanced tumor penetration. Int J Biol Macromol. 2024;271:132626. https://doi.org/10.1016/j.ijbiomac.2024.132626. source

In the paper

“PEG-CPP33-decorated zeolitic imidazolate framework-90 (ZIF-90) MOFs co-deliver small molecules and siRNA with acid-triggered release and improved lysosomal escape to produce chemo-gene synergy [66].”

What the sources say

• ?Not checked — no full text of the sourcecites [66] Cai M, Yao Y, Yin D, Zhu R, Fu T, Kong J, et al. Enhanced lysosomal escape of cell penetrating peptide-functionalized metal-organic frameworks for co-delivery of survivin siRNA and oridonin. J Colloid Interface Sci. 2023;646:370–80. https://doi.org/10.1016/j.jcis.2023.04.126. source

In the paper

“In addition, when the activated entities approach the ultrasmall range, concentration gradients can drive partial back-diffusion toward vessels, and systemic elimination can accelerate once fragments re-enter circulation, collectively increasing the risk of intratumoral washout.”

What the sources say

• ?Not checked — no full text of the sourcecites [22] He Y, Fan X, Wu X, Hu T, Zhou F, Tan S, et al. pH-responsive size-shrinkable mesoporous silica-based nanocarriers for improving tumor penetration and therapeutic efficacy. Nanoscale. 2022;14:1271–84. https://doi.org/10.1039/d1nr07513f. source
• ?Not checked — no full text of the sourcecites [24] Ma T, Li W, Ye J, Huang C, Li Y, Qiu H, et al. GSH/pH dual response drug delivery system for photothermal enhanced gene-immunotherapy. Nanoscale. 2023;15:16947–58. https://doi.org/10.1039/d3nr03881e. source

In the paper

“These sources of heterogeneity lead to variable activation thresholds and increase the risk of premature, incomplete or misplaced transformation, particularly for single-stimulus systems; multi-stimulus designs can mitigate this at the cost of added synthetic and analytical complexity.”

In the paper

“A silicasome that delivers the multi-target TKI nintedanib increases intratumoral drug exposure, prunes aberrant vessels, reduces collagen, elevates the CD8⁺/FoxP3⁺ ratio, and enables synergy with anti-PD-1 in a robust orthotopic pancreatic cancer model [45]”

What the sources say

• Not checked yetcites [45] Luo L, Wang X, Liao YP, Xu X, Chang CH, Nel AE. Reprogramming the pancreatic cancer stroma and immune landscape by a silicasome nanocarrier delivering nintedanib, a protein tyrosine kinase inhibitor. Nano Today. 2024;54:102058. https://doi.org/10.1016/j.nantod.2023.102058. source

In the paper

“Compared with shrink-only designs, these systems increase cell engagement and adsorption-mediated transcytosis, elevating uptake where membrane passage is rate-limiting.”

In the paper

“Aligning the sequence of transformations with the expected perfusion window, for example ensuring that contraction precedes cation exposure while perfusion is still adequate, further improves spatial uniformity and pharmacodynamics.”

In the paper

“To clarify comparator context, the source reports BBB penetration of ~ 50% (≈10 × vs GeNPs) and spheroid penetration distance of ~ 416 μm (≈2.8 × vs GeNPs).”

What the sources say

• Check pendingcites [64] Gao Y, Mao M, Li Y, Xuan M, Wu Y, He Q. A self-directed trojanbot-enzymatic nanobot in neutrobot for active target therapy of glioblastoma. Nat Commun. 2025;16:5263. https://doi.org/10.1038/s41467-025-60422-z. source

In the paper

“Exosome and membrane preparations often exhibit batch-to-batch variability in vesicle size, lipid and protein composition and functional marker expression, and their activity is highly sensitive to isolation methods, storage conditions and freeze thaw cycles.”

What the sources say

• Check pendingcites [71] Verma N, Arora S. Navigating the global regulatory landscape for exosome-based therapeutics: challenges, strategies, and future directions. Pharmaceutics. 2025;17:990. https://doi.org/10.3390/pharmaceutics17080990. source

In the paper

“Scaling up production under GMP conditions is further complicated by the need for large, well-characterized cell banks or microbial strains and robust in-process controls, and by the multi-origin nature of many hybrid constructs, which blurs the boundary between biologics, devices and combination products in current regulatory frameworks [72].”

What the sources say

• ?Not checked — no full text of the sourcecites [72] Ilgin K-G, Suphi SO. Exosomes: large-scale production, isolation, drug loading efficiency, and biodistribution and uptake. J Control Release. 2022;347:533–43. https://doi.org/10.1016/j.jconrel.2022.05.027. source

In the paper

“Wan et al. reviewed β‑carboxylic amide-based DMMA shields, which remain stealthy in circulation but hydrolyze under acidic conditions to expose cationic surfaces, facilitating higher uptake while highlighting challenges in stability and manufacturability [26].”

What the sources say

• Check pendingcites [26] Wan D, Wu Y, Liu Y, Liu Y, Pan J. Advances in 2,3-dimethylmaleic anhydride (DMMA)-modified nanocarriers in drug delivery systems. Pharmaceutics. 2024;16:809. https://doi.org/10.3390/pharmaceutics16060809. source

In the paper

“Fusing the nucleolin targeted F3 peptide to trimeric TRAIL creates a multivalent construct that improves tumor penetration and strengthens death receptor signaling, lowering IC50 values by about ten to 40- fold across several tumor lines and reducing tumor weight in vivo versus TRAIL alone [82].”

What the sources say

• ?Not checked — no full text of the sourcecites [82] Lopes R, Shi K, Fonseca NA, Gama A, Ramalho JS, Almeida L, et al. Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin. Drug Deliv Transl Res. 2022;12:629–46. https://doi.org/10.1007/s13346-021-00972-z. source

In the paper

“Together, these examples illustrate that normalization can be achieved by vascular support, junctional stabilization or selective pathway interruption, but all require careful control of dose and timing to preserve perfusion while lowering transport resistance.”

In the paper

“Bioluminescence decreased most at days 7 and 14, outperforming free TMZ, T7/TMZ micelles, or neutrophils alone, with no added toxicity [65].”

What the sources say

• Check pendingcites [65] Piao C, Lee J, Kim GE, Choe YH, Lee H, Hyun YM. Targeted delivery of nanoparticle-conveyed neutrophils to the glioblastoma site for efficient therapy. ACS Appl Mater Interfaces. 2024;16:41819–27. https://doi.org/10.1021/acsami.4c05691. source

In the paper

“Collagenase-armed CMSNs traverse millimeter-scale collagenous stroma in small pancreatic xenografts (penetration ≥ 1.2 mm across the stromal compartment) and increase doxorubicin delivery [49]”

What the sources say

• ?Not checked — no full text of the sourcecites [49] Qiu N, Lv QY, Li CL, Song X, Wang YQ, Chen J, et al. Optimization and mechanisms of proteolytic enzyme immobilization onto large-pore mesoporous silica nanoparticles: enhanced tumor penetration. Int J Biol Macromol. 2024;271:132626. https://doi.org/10.1016/j.ijbiomac.2024.132626. source

In the paper

“As summarized in Fig. 1, barrier-overcoming platforms primarily operate at the vascular and ECM/IFP levels and usually represent the earliest step in the temporal sequence (priming before carrier transformation and payload activation).”

In the paper

“Collagenase-loaded hydrogenated TiO₂ nanoparticles softened collagen-rich tumor stroma, improved ultrasound imaging guidance, and augmented sonodynamic therapy by enabling deeper intratumoral penetration and drug action with therapeutic enhancement reported versus non-collagenase nanoparticle [58].”

What the sources say

• ?Not checked — no full text of the sourcecites [58] Luo J, Cao J, Ma G, Wang X, Sun Y, Zhang C, et al. Collagenase-loaded H-TiO2 nanoparticles enhance ultrasound imaging-guided sonodynamic therapy in a pancreatic carcinoma xenograft model via digesting stromal barriers. ACS Appl Mater Interfaces. 2022;14:40535–45. https://doi.org/10.1021/acsami.2c08951. source

In the paper

“Upon HAase digestion in the tumor bed, the shell is removed, shrinking the particles to approximately 130 nm and reversing the surface charge to positive.”

What the sources say

• ?Not checked — no full text of the sourcecites [25] Hu J, Zhou W, Zhou Y, Hu H, Ran S, Zhang Y. Ph-independent charge-reversal strategy for enhanced tumor penetration based on hyaluronidase-responsive tellurium-containing polycarbonate nanocarriers. J Mater Chem B. 2025;13:8483–95. https://doi.org/10.1039/d5tb00368g. source

In the paper

“As discussed above, however, the formation and remodeling of a protein corona in vivo may delay or dampen these sequential switches, making it essential to benchmark dual-transform systems under realistic protein conditions rather than only in simple buffers.”

In the paper

“These considerations suggest that the most useful design space is often not “as small as possible’ but rather ‘small enough to move, yet large/interactive enough to stay”, motivating staged architectures that diffuse first and capture later.”

In the paper

“Across materials classes (MOFs, elastin-like polypeptides, polymeric micelles, mesoporous silica), CPPs consistently shift the rate-limiting step from membrane access to intracellular trafficking, with brain-directed designs further exploiting adsorptive-mediated transcytosis (AMT) and efflux modulation.”

In the paper

“Conceptually, effective designs now couple a short perfusion window with matrix softening or pressure relief, then layer cellular uptake and immune activation so that distribution and action are temporally aligned.”

In the paper

“From a safety perspective, CPP-containing and other strongly cationic nanoparticles increase the risk of dose-dependent cytotoxicity, hemolysis, complement activation and non-specific adsorption to plasma proteins and vascular endothelium, which can trigger undesired uptake in the blood circulation, rapid RES sequestration and increased exposure of healthy tissues [76].”

What the sources say

• Check pendingcites [76] Khorsand Zak A, Hashim AM, Khorsand Zak H. Investigating the cytotoxicity of aluminum-doped zinc oxide nanoparticles in normal versus cancerous breast cells. Sci Rep. 2025;15:25227. https://doi.org/10.1038/s41598-025-11373-4. source

In the paper

“For BBB traversal and deep brain delivery, neutrophil “Trojanbots” encapsulated catalase-powered gelatin nanobots (CatNbots). The assemblies measured about 329 nm (ζ ~ − 35.6 mV), crossed an in vitro BBB with roughly 50% efficiency, and once released self-propelled about 416 μm through GL261 spheroids.”

What the sources say

• Check pendingcites [64] Gao Y, Mao M, Li Y, Xuan M, Wu Y, He Q. A self-directed trojanbot-enzymatic nanobot in neutrobot for active target therapy of glioblastoma. Nat Commun. 2025;16:5263. https://doi.org/10.1038/s41467-025-60422-z. source

In the paper

“Engineered bacteria that secrete hyaluronidase degrade hyaluronan in situ, reduce interstitial fluid pressure, and potentiate chemotherapy in breast and pancreatic tumor models with survival extension [69].”

What the sources say

• ?Not checked — no full text of the sourcecites [69] Kim JS, Park JE, Choi SH, Kang SW, Lee JH, Lee JS, et al. ECM-targeting bacteria enhance chemotherapeutic drug efficacy by lowering IFP in tumor mouse models. J Control Release. 2023;355:199–210. https://doi.org/10.1016/j.jconrel.2023.02.001. source

In the paper

“Neutrophil “Trojanbots” and PMN/T7/TMZ carriers, by contrast, exploit active homing and BBB transmigration to distribute payloads widely within orthotopic glioma; they offer superior brain delivery and survival benefit, at the price of more demanding cell sourcing, processing and quality control.”

In the paper

“Biologically, performance and safety may be impacted by unintended immune activation and inflammatory toxicities, including premature neutrophil activation and NETosis, off-target tissue injury, altered trafficking/biodistribution, and inflammation-dependent variability across disease states and patients.”

In the paper

“A representative construct (PLGA-STM-TAT@CCM-YSA) illustrates this pattern, preferential deposition with transcriptional rewiring and anti-PD-1 synergy [61].”

What the sources say

• ?Not checked — no full text of the sourcecites [61] Li Z, Zhang X, Liu C, Wu Y, Wen Y, Zheng R, et al. Engineering a nano-drug delivery system to regulate m6A modification and enhance immunotherapy in gastric cancer. Acta Biomater. 2025;191:412–27. https://doi.org/10.1016/j.actbio.2024.11.036. source

In the paper

“As summarized in Table 1, most transformable nanocarriers are calibrated in well-controlled rodent models or 3D spheroids with relatively uniform stimuli, whereas human tumors display pronounced microregional heterogeneity in extracellular pH, enzyme activity and hypoxia.”

What the sources say

• Check pendingcites [31] Xiao P, Huang J, Han X, Cheu JWS, Liu Y, Law LH, et al. Monitor tumor pHe and response longitudinally during treatment using CEST MRI-detectable alginate microbeads. ACS Appl Mater Interfaces. 2022;14:54401–10. https://doi.org/10.1021/acsami.2c10493. source
• Check pendingcites [32] Tang Y, Xiao G, Shen Z, Zhuang C, Xie Y, Zhang X, et al. Noninvasive detection of extracellular pH in human benign and malignant liver tumors using CEST MRI. Front Oncol. 2020;10:578985. https://doi.org/10.3389/fonc.2020.578985. source

In the paper

“Ligand-functionalized platforms add active binding, trans-barrier transport, and facilitated uptake to improve selectivity and distribution [79] (Fig. 5).”

What the sources say

• Check pendingcites [79] Kim M, Shin M, Zhao Y, Ghosh M, Son YO. Transformative impact of nanocarrier-mediated drug delivery: overcoming biological barriers and expanding therapeutic horizons. Small Sci. 2024;4:2400280. https://doi.org/10.1002/smsc.202400280. source

In the paper

“Wu et al. exploited a bispecific precursor peptide (pre‑GP1) that binds neuropilin‑1 and PD‑L1, self‑assembling in situ into β‑sheet “fibrous glue.””

What the sources say

• ?Not checked — no full text of the sourcecites [46] Wu XH, Wang JQ, Wang MD, Xiao T, Wang Y, Niu JY, et al. Bispecific fibrous glue synergistically boosts vascular normalization and antitumor immunity for advanced renal carcinoma therapy. Biomaterials. 2024;308:122550. https://doi.org/10.1016/j.biomaterials.2024.122550. source

In the paper

“Membrane-disrupting polymers (e.g., amphiphiles inserting into lipid bilayers) can weaken cell–cell junctions and induce NanoEL-like permeability, as quantified by TEER decline and Transwell leakage, thereby facilitating deeper transport and subsequent therapy [70].”

What the sources say

• Not checked yetcites [70] Yalamandala BN, Chen YJ, Lin YH, Huynh TMH, Chiang WH, Chou TC, et al. A self-cascade penetrating brain tumor immunotherapy mediated by near-infrared II cell membrane-disrupting nanoflakes via detained dendritic cells. ACS Nano. 2024;18:18712–28. https://doi.org/10.1021/acsnano.4c06183. source

In the paper

“Dendritic-cell macrovesicles loaded with VEGF-A siRNA and doxorubicin conserved CD9/CD63/CD81, enhanced uptake and normalized the vascular bed, curbing vasculogenic mimicry and drawing perivascular T cells in orthotopic glioma [62].”

What the sources say

• ?Not checked — no full text of the sourcecites [62] Shamshiripour P, Rahnama M, Nikoobakht M, Rad VF, Moradi AR, Ahmadvand D. Extracellular vesicles derived from dendritic cells loaded with VEGF-A siRNA and doxorubicin reduce glioma angiogenesis in vitro. J Control Release. 2024;369:128–45. https://doi.org/10.1016/j.jconrel.2024.03.042. source

In the paper

“Ligand- and transcytosis-mediated systems occupy the “receptor-guided” branch in Fig. 1, where trigger-gated ligand exposure and CendR-mediated transcytosis govern vascular crossing and interstitial spread.”

In the paper

“Enzyme-powered platelet micromotors mainly enhance local convection and cellular uptake after intratumoral administration, providing strong radiosensitization with limited systemic exposure but also constrained reach beyond the injection field.”

In the paper

“Platelet micromotors (PLT@Au@Urease) carried about 29 pg of Au radiosensitizer per platelet and showed zeta potential near − 17.5 mV.”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Liu W, Nie H, Li H, Liu Y, Tian M, Wang S, et al. Engineered platelet cell motors for boosted cancer radiosensitization. J Colloid Interface Sci. 2024;658:540–52. https://doi.org/10.1016/j.jcis.2023.12.091. source

In the paper

“Dose and timing are critical, because excessive or prolonged anti-angiogenic exposure may reduce perfusion and counteract delivery, whereas short regimens can transiently enhance transport and thereby augment charge-reversal gains.”

In the paper

“This process enhances adsorption-mediated transcytosis, allowing uniform penetration through 3.6 mm thick 2,3-Dimethylmaleic Anhydride (DMMA) xenografts and achieving potent tumor inhibition via mitochondrial cisplatin release with negligible systemic toxicity compared with the control groups [25].”

What the sources say

• ?Not checked — no full text of the sourcecites [25] Hu J, Zhou W, Zhou Y, Hu H, Ran S, Zhang Y. Ph-independent charge-reversal strategy for enhanced tumor penetration based on hyaluronidase-responsive tellurium-containing polycarbonate nanocarriers. J Mater Chem B. 2025;13:8483–95. https://doi.org/10.1039/d5tb00368g. source

In the paper

“Clinical imaging and microelectrode studies indicate that the bulk extracellular pH of many solid tumors often remains around 6.8–7.1, with only patchy acidic niches falling below 6.7, so pH-triggered shrinkers or charge-reversal systems tuned to sharp transitions at pH 6.5–6.8 may transform efficiently in small, severely hypoxic regions but remain inactive in large portions of the lesion [31, 32]”

What the sources say

• Not checked yetcites [31] Xiao P, Huang J, Han X, Cheu JWS, Liu Y, Law LH, et al. Monitor tumor pHe and response longitudinally during treatment using CEST MRI-detectable alginate microbeads. ACS Appl Mater Interfaces. 2022;14:54401–10. https://doi.org/10.1021/acsami.2c10493. source
• Not checked yetcites [32] Tang Y, Xiao G, Shen Z, Zhuang C, Xie Y, Zhang X, et al. Noninvasive detection of extracellular pH in human benign and malignant liver tumors using CEST MRI. Front Oncol. 2020;10:578985. https://doi.org/10.3389/fonc.2020.578985. source

In the paper

“Second, depot followed by regeneration strategies, where amphiphiles form small, blood-stable particles that precipitate at pH about 6.5 to create a local depot and subsequently hydrolyze to regenerate tens-of-nanometers, folate-targeted cationic spheres for sustained deep delivery [30].”

What the sources say

• ?Not checked — no full text of the sourcecites [30] Sun J, Wang Y, Zhang J, Wang J, Wang C. A drug reservoir strategy for long-acting cancer therapy using morphologically transformed amphiphilic polymeric nanoparticles. Acta Biomater. 2025;202:435–49. https://doi.org/10.1016/j.actbio.2025.07.006. source

In the paper

“Despite these advances, each modality carries intrinsic limitations. Enzyme-based ECM depletion may risk off-target proteolysis or compensatory fibrosis; vascular normalization is transient and dose-sensitive; and spatial heterogeneity in TME composition complicates universal trigger design.”

In the paper

“Dendritic polymer-based nanomedicines that phenotypically reprogram cancer-associated fibroblasts and decompress tumor vessels provide a complementary stromal-normalizing route, lowering solid stress, increasing perfusion and CD8⁺ T-cell infiltration, and thereby improving the efficacy of immune checkpoint blockade in desmoplastic lung tumors”

What the sources say

• ?Not checked — no full text of the sourcecites [57] Zhang Y, Fang Z, Pan D, Li Y, Zhou J, Chen H, et al. Dendritic polymer-based nanomedicines remodel the tumor stroma: improve drug penetration and enhance antitumor immune response. Adv Mater. 2024;36:e2401304. https://doi.org/10.1002/adma.202401304. source

In the paper

“pre-GP1 “fibrous glue” | Bispecific peptide binding to NRP1 and PD-L1; in situ beta-sheet nanofiber assembly; vascular support | Preclinical renal carcinoma models | Vascular instability and perivascular immune exclusion | 3D tumor spheroids: permeability factor increased by 6 times | Tumor inhibition rate 60.90% | [46]”

What the sources say

• ?Not checked — no full text of the sourcecites [46] Wu XH, Wang JQ, Wang MD, Xiao T, Wang Y, Niu JY, et al. Bispecific fibrous glue synergistically boosts vascular normalization and antitumor immunity for advanced renal carcinoma therapy. Biomaterials. 2024;308:122550. https://doi.org/10.1016/j.biomaterials.2024.122550. source

In the paper

“Hypoxia-reduced charge-switch micelles that concurrently trigger transcytosis and stromal remodeling stand out for depth of transport, reaching beyond 400 µm in dense pancreatic tumors and providing robust chemo-immunotherapy synergy, but they also exemplify the highest level of formulation complexity.”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Zhang S, You H, Fan H, Chen Y, Song H, Zhao Z, et al. Transcytosis-triggering nanoparticles for overcoming stromal barriers and reversing immunosuppression in pancreatic cancer combinatorial therapy. Nano Lett. 2025;25:2949–59. https://doi.org/10.1021/acs.nanolett.4c06372. source

In the paper

“Third, adapt particle size and multivalency to stromal state; small, lightly multivalent constructs should be favored in early, looser matrix, while larger and more multivalent formats can exploit receptor clustering in late, collagen-dense lesions.”

In the paper

“Hierarchical micelles for curcumin and doxorubicin | pH and enzyme | Biotin-channeled curcumin prodrug micelles with doxorubicin | Stage pH then enzyme response; P-gp inhibition first; doxorubicin release next”

What the sources say

• ?Not checked — no full text of the sourcecites [99] Das M, Joshi A, Devkar R, Seshadri S, Thakore S. Vitamin-H channeled self-therapeutic P-gp inhibitor curcumin-derived nanomicelles for targeting the tumor milieu by pH- and enzyme-triggered hierarchical disassembly. Bioconjug Chem. 2022;33:369–85. https://doi.org/10.1021/acs.bioconjchem.1c00614. source

In the paper

“Hierarchical micelles and “hairy” molecularly imprinted nanocapsules integrate recognition and multi-step disassembly, resulting in deeper spheroid penetration and sustained intratumoral retention, yet they require multiple orthogonal linkers and non-trivial synthetic routes [110].”

What the sources say

• ?Not checked — no full text of the sourcecites [110] Zhou Y, Mu Y, Zhang H. Efficient synthesis of hydrophilic hairy semihollow molecularly imprinted polymer microcapsules with ultrahigh drug loading and pH-responsive sustained release properties. ACS Appl Mater Interfaces. 2025;17:65495–508. https://doi.org/10.1021/acsami.5c19502. source

In the paper

“Method oriented analyses compare D and L peptide isoforms and outline modifications such as retro inverso and cyclization that influence stability and performance of tumor homing peptides, providing options to enhance CendR carriers.”

In the paper

“Core–shell MOF@poly(ortho ester) structures lose the acid-labile shell in the TME and switch surface potential from negative to positive, supporting nuclear-proximal delivery [97].”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Hu L, Xiong C, Wei G, Yu Y, Li S, Xiong X, et al. Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer. J Colloid Interface Sci. 2022;608:1882–93. https://doi.org/10.1016/j.jcis.2021.10.070. source

In the paper

“pH and MMP-9 responsive liposomes co-delivering the galectin-3 inhibitor GB1107, the PD-1 inhibitor BMS-1166, and enzalutamide to remodel the immune TME and reverse T-cell exhaustion [103, 104].”

What the sources say

• Check pendingcites [103] Du JR, Teng DK, Wang Y, Wang Q, Lin YQ, Luo Q, et al. Endogenous H2O2 self-replenishment and sustainable cascades enhance the efficacy of sonodynamic therapy. Int J Nanomed. 2023;18:6667–87. https://doi.org/10.2147/IJN.S431221. source
• Check pendingcites [104] Lu S, Zhang C, Wu H, Wang J, Wang J, Zhao L, et al. A pH/MMP-9 smart dual-responsive liposome GBE@LP co-delivers and controls the release of GB1107/BMS1166/Enzalutamide for liver cancer immunotherapy. Mater Today Bio. 2025;32:101801. https://doi.org/10.1016/j.mtbio.2025.101801. source

In the paper

“Modeling indicates that sub-50 nm dimensions favor diffusion, whereas interstitial fluid retention elevates IFP and shapes uptake fields, underscoring the need to co-optimize particle physics with tumor hydraulics [105, 108, 115].”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Zhang S, You H, Fan H, Chen Y, Song H, Zhao Z, et al. Transcytosis-triggering nanoparticles for overcoming stromal barriers and reversing immunosuppression in pancreatic cancer combinatorial therapy. Nano Lett. 2025;25:2949–59. https://doi.org/10.1021/acs.nanolett.4c06372. source
• ?Not checked — no full text of the sourcecites [108] Jafari-Matanagh S, Razavi SE, Ehghaghi Bonab MB, Omidian H, Omidi Y. Multi-dimensional modeling of nanoparticles transportation from capillary bed into the tumor microenvironment. Comput Biol Med. 2023;152:106477. https://doi.org/10.1016/j.compbiomed.2022.106477. source
• ?Not checked — no full text of the sourcecites [115] Yang Y, Chen K, He X, Han H, Li L, Li M, et al. Nanoscale gambogic acid liposomes for NIR-II photoacoustic imaging and photothermal-chemo tumor therapy. ACS Appl Nano Mater. 2024;7:17688–96. https://doi.org/10.1021/acsanm.4c02918. source

In the paper

“Membrane-disrupting amphiphiles can weaken cell–cell junctions and induce NanoEL-like permeability.”

In the paper

“This “prime-first, deliver-second” choreography widens the perfusion window and reduces matrix drag before intracellular action.”

In the paper

“the tumor inhibition rate reached ~ 84.14% for the GA-targeted cascade system versus ~ 70.88% (non-GA nanoparticle control), ~ 64.87% (free drug), and ~ 22.67% (saline).”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Shi J, Wang Y, Wu Y, Li J, Fu C, Li Y, et al. Tumor microenvironment ROS/pH cascade-responsive supramolecular nanoplatform with ROS regeneration property for enhanced hepatocellular carcinoma therapy. ACS Appl Mater Interfaces. 2024;16:7576–92. https://doi.org/10.1021/acsami.3c16022. source

In the paper

“HA or MMP-2 cleavable coated size-shrinkable system | Enzyme and pH | HA or MMP-2 cleavable shell with CD44 recognition; doxorubicin payload | Long circulation; shell shedding contracts size from about 150 nm to about 50 nm at tumor; pH-guided drug release”

What the sources say

• ?Not checked — no full text of the sourcecites [96] Dai W, Zhou X, Zhao J, Lei L, Huang Y, Jia F, et al. Tumor microenvironment-modulated nanoparticles with cascade energy transfer as internal light sources for photodynamic therapy of deep-seated tumors. Biomaterials. 2025;312:122743. https://doi.org/10.1016/j.biomaterials.2024.122743. source

In the paper

“Recent studies indicate that corona composition is highly context-dependent and can re-mask targeting ligands or pH/redox-sensitive linkers, effectively broadening or shifting activation windows compared with corona-free buffer conditions.”

What the sources say

• ?Not checked — no full text of the sourcecites [119] Debnath M, Forster J, Ramesh A, Kulkarni A. Protein corona formation on lipid nanoparticles negatively affects the NLRP3 inflammasome activation. Bioconjug Chem. 2023;34:1766–79. https://doi.org/10.1021/acs.bioconjchem.3c00329. source

In the paper

“ROS and pH cascade-responsive supramolecular nanoparticles | H2O2 and low pH | GA-targeted host–guest assembly carrying triptolide | Size decrease from about 181 nm to about 125 nm; zeta potential switches from about − 2.8 mV to about + 15.4 mV; accelerated entry and burst release”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Shi J, Wang Y, Wu Y, Li J, Fu C, Li Y, et al. Tumor microenvironment ROS/pH cascade-responsive supramolecular nanoplatform with ROS regeneration property for enhanced hepatocellular carcinoma therapy. ACS Appl Mater Interfaces. 2024;16:7576–92. https://doi.org/10.1021/acsami.3c16022. source

In the paper

“Paclitaxel-IR780 platform with GSH-responsive release | Photothermal priming and GSH | Paclitaxel conjugate or formulation with IR780; redox-cleavable linker | Photothermal heating increases permeability; intracellular GSH triggers paclitaxel release; chemo-photothermal synergy”

What the sources say

• ?Not checked — no full text of the sourcecites [102] Dai Q, Du Z, Jing L, Zhang R, Tang W. Enzyme-responsive modular peptides enhance tumor penetration of quantum dots via charge reversal strategy. ACS Appl Mater Interfaces. 2024;16:6208–20. https://doi.org/10.1021/acsami.3c11500. source

In the paper

“In an endothelial monolayer model (bEnd.3), TEER decreased at 6 and 24 h after nanoparticle exposure, and Transwell assays and CLSM confirmed partial leakage across the cell sheet, supporting barrier loosening that can facilitate deeper transport.”

In the paper

“3D spheroid z-stack signal: ~ 120 µm;tumor inhibition rate: 31%”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Hu L, Xiong C, Wei G, Yu Y, Li S, Xiong X, et al. Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer. J Colloid Interface Sci. 2022;608:1882–93. https://doi.org/10.1016/j.jcis.2021.10.070. source

In the paper

“Pegylated liposomal doxorubicin (Doxil/Caelyx), for instance, showed similar efficacy endpoints with significantly reduced cardiotoxicity versus conventional doxorubicin in metastatic breast cancer, illustrating that the most consistent clinical value may be toxicity mitigation and exposure smoothing rather than reliably deeper parenchymal penetration[123].”

What the sources say

• Check pendingcites [123] Upshaw JN, Parson SK, Buchsbaum RJ, Schlam I, Ruddy KJ, Durani U, et al. Dexrazoxane to prevent cardiotoxicity in adults treated with anthracyclines. JACC: CardioOncology. 2024;6:322–4. https://doi.org/10.1016/j.jaccao.2024.02.004. source

In the paper

“Multilayer constructs and orthogonal linkers raise manufacturability and reproducibility demands; heterogeneous stimuli risk premature disassembly or under-activation; binding-site barriers and the protein corona can trap carriers near vessels.”

In the paper

“For lipid- and polymer-based nanoparticles, controlled and reproducible assembly (e.g., continuous or in-line mixing approaches) combined with in-process analytics can improve batch-to-batch consistency.”

In the paper

“The guiding logic mirrors “long circulation, local activation”: carriers remain stable in blood, then switch at the tumor to deepen diffusion and synchronize payload action [94].”

What the sources say

• Check pendingcites [94] Fang F, Wang S, Song Y, Sun M, Chen WC, Zhao D, et al. Continuous spatiotemporal therapy of a full-API nanodrug via multi-step tandem endogenous biosynthesis. Nat Commun. 2023;14:1660. https://doi.org/10.1038/s41467-023-37315-0. source

In the paper

“For example, mice receiving ONC201@WINA + HFMF plus anti-PD-1 showed the most pronounced survival benefit versus PBS and single-therapy controls, consistent with enhanced T-cell infiltration and improved checkpoint blockade responsiveness [117].”

What the sources say

• ?Not checked — no full text of the sourcecites [117] Thrinayan M, Chia-Ko C, Zhuo-Hao L, Bhanu Nirosha Y, Thi My Hue H, Hoi Man I, et al. Wireless chargeable gold yarnball-mediated mitochondrial depolarization for dendritic cell detainment in programmed brain tumor immunotherapy. Nano Today. 2025;65:102838. https://doi.org/10.1016/j.nantod.2025.102838. source

In the paper

“Ferritin nanocages use EPR and transferrin receptor 1 for accumulation and entry, then unmask an MMP-2/9 cleavable anti-PD-L1 peptide in the matrix and release oxaliplatin under lysosomal pH, improving chemoimmunotherapy with spatial control [107].”

What the sources say

• ?Not checked — no full text of the sourcecites [107] Liu Z, Hao X, Qian J, Zhang H, Bao H, Yang Q, et al. Enzyme/pH dual-responsive engineered nanoparticles for improved tumor immuno-chemotherapy. ACS Appl Mater Interfaces. 2024;16:12951–64. https://doi.org/10.1021/acsami.3c18348. source

In the paper

“From a scalability perspective, translation favors architectures with fewer unique components and modular chemistries that preserve CQAs during scale-up.”

In the paper

“Strategies such as reducing intrinsic affinity, lowering ligand copy number, or optimizing spatial presentation allow carriers to bypass perivascular sequestration and achieve deeper interstitial penetration [93].”

What the sources say

• Check pendingcites [93] Yang W, Hicks DR, Ghosh A, Schwartze TA, Conventry B, Goreshnik I, et al. Design of high-affinity binders to immune modulating receptors for cancer immunotherapy. Nat Commun. 2025;16:2001. https://doi.org/10.1038/s41467-025-57192-z. source

In the paper

“Notably, in 4T1 tumor-bearing mice, DTX/RGD NPs yielded 0/6 tumors exceeding 600 mm3 at day 20 (vs 6/6 saline, 6/6 blank NPs, 4/6 free DTX, 3/6 DTX/PLGA NPs), and no metastatic clots were observed in lung after DTX/RGD NP treatment (vs abundant nodules in saline/blank groups)”

What the sources say

• Check pendingcites [83] Yao P, Wang X, Wang Q, Dai Q, Peng Y, Yuan Q, et al. Cyclic RGD-functionalized pH/ROS dual-responsive nanoparticle for targeted breast cancer therapy. Pharmaceutics. 2023;15:1827. https://doi.org/10.3390/pharmaceutics15071827. source

In the paper

“Mechanistically, limited survival translation is commonly associated with heterogeneous EPR/perfusion across patients and lesions, low and variable tumor deposition, perivascular sequestration and binding-site barriers, and carrier/PK designs that do not ensure adequate bioavailable drug release at depth, together with systemic clearance by the mononuclear phagocyte system [124].”

What the sources say

• ?Not checked — no full text of the sourcecites [124] Gomerdinger VF, Nabar N, Hammond PT. Advancing engineering design strategies for targeted cancer nanomedicine. Nat Rev Cancer. 2025;25:657–83. https://doi.org/10.1038/s41568-025-00847-2. source

In the paper

“Acid-induced sphere-to-fiber assemblies | Acidic pH | Dual-drug supramolecular assembly | Long circulation; sphere-to-fiber transition at tumor; prolonged residence and synchronized exposure”

What the sources say

• Check pendingcites [106] Liu Y, Liu Y, Sun X, Wang Y, Du C, Bai J. Morphologically transformable peptide nanocarriers coloaded with doxorubicin and curcumin inhibit the growth and metastasis of hepatocellular carcinoma. Mater Today Bio. 2024;24:100903. https://doi.org/10.1016/j.mtbio.2023.100903. source

In the paper

“In this system, MMP-1 and MMP-2 were upregulated by ~ 5.7 × and ~ 5.1 × (vs PBS), while collagen I was reduced to ~ 46% of the PBS group, quantitative remodeling that mechanistically supports the reported penetration gains rather than relying on qualitative imaging alone.”

What the sources say

• Check pendingcites [101] Li D, Chen X, Dai W, Jin Q, Wang D, Ji J, et al. Photo-triggered cascade therapy: a NIR-II AIE luminogen collaborating with nitric oxide facilitates efficient collagen depletion for boosting pancreatic cancer phototheranostics. Adv Mater. 2024;36:e2306476. https://doi.org/10.1002/adma.202306476. source

In the paper

““Hairy” molecularly imprinted nanocapsules for sialic acid | Mildly acidic pH and GSH | SA-imprinted capsules with benzoic imine brushes and disulfide crosslinks; 5-fluorouracil model | Brush shedding exposes SA sites and flips surface charge to positive; intracellular GSH degrades shell for rapid release”

What the sources say

• Check pendingcites [100] Zhang H, Mu Y, Han C, Zhou Y. Multi-responsive molecularly imprinted polymer nanocapsules as biological environment-adaptable drug carriers for efficient cancer therapy. Small. 2025;21:e2412303. https://doi.org/10.1002/smll.202412303. source

In the paper

“ROS/pH cascades detach β-cyclodextrin shells, shrink size (~ 181 to ~ 125 nm), and flip ζ potential (− 2.8 to + 15.4 mV), which accelerates triptolide entry and burst release at depth [98].”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Shi J, Wang Y, Wu Y, Li J, Fu C, Li Y, et al. Tumor microenvironment ROS/pH cascade-responsive supramolecular nanoplatform with ROS regeneration property for enhanced hepatocellular carcinoma therapy. ACS Appl Mater Interfaces. 2024;16:7576–92. https://doi.org/10.1021/acsami.3c16022. source

In the paper

“And “hairy” molecularly imprinted polymer nanocapsules that shed benzoic imine brushes in acidic TME to expose sialic acid sites, switch charge, and then disulfide degrade for rapid payload release and deep spheroid penetration [100].”

What the sources say

• Check pendingcites [100] Zhang H, Mu Y, Han C, Zhou Y. Multi-responsive molecularly imprinted polymer nanocapsules as biological environment-adaptable drug carriers for efficient cancer therapy. Small. 2025;21:e2412303. https://doi.org/10.1002/smll.202412303. source

In the paper

“Overall, systems with more orthogonal triggers and integrated stromal modulation tend to deliver the best combination of penetration and therapeutic benefit, whereas simpler single-trigger designs offer easier translation but more modest gains, highlighting a continuum between performance and manufacturability [111].”

What the sources say

• Check pendingcites [111] Guo X, Han L, Chen W, He H, Zhang W, Huang C, et al. Hypoxia and singlet oxygen dual-responsive micelles for photodynamic and chemotherapy therapy featured with enhanced cellular uptake and triggered cargo delivery. Int J Nanomedicine. 2024;19:247–61. https://doi.org/10.2147/IJN.S432407. source

In the paper

“In the eye, iRGD, RPARPAR, and PL3 traverse from choroid through the retinal pigment epithelium to the outer nuclear layer and cut leakage by about fifty percent in a laser induced choroidal neovascularization model [90].”

What the sources say

• ?Not checked — no full text of the sourcecites [90] Puranen J, Korhonen S, Haugas M, Lingasamy P, Teesalu T, Subrizi A, et al. Intravitreal CendR peptides target laser-induced choroidal neovascularization sites in mice. J Control Release. 2023;360:810–7. https://doi.org/10.1016/j.jconrel.2023.07.025. source

In the paper

“pH and MMP-9 responsive liposomes co-delivering GB1107, BMS1166, enzalutamide (GBE@LP) | Acidic pH and MMP-9 | PEGylated liposomes with immuno-modulators | Long circulation; tumor-site release; immune TME remodeling; reversal of T-cell exhaustion”

What the sources say

• Check pendingcites [104] Lu S, Zhang C, Wu H, Wang J, Wang J, Zhao L, et al. A pH/MMP-9 smart dual-responsive liposome GBE@LP co-delivers and controls the release of GB1107/BMS1166/Enzalutamide for liver cancer immunotherapy. Mater Today Bio. 2025;32:101801. https://doi.org/10.1016/j.mtbio.2025.101801. source

In the paper

“Hierarchical micelles can stage pH then enzyme responses to liberate curcumin for P-gp inhibition and amplify doxorubicin against multidrug-resistant lesions [99].”

What the sources say

• ?Not checked — no full text of the sourcecites [99] Das M, Joshi A, Devkar R, Seshadri S, Thakore S. Vitamin-H channeled self-therapeutic P-gp inhibitor curcumin-derived nanomicelles for targeting the tumor milieu by pH- and enzyme-triggered hierarchical disassembly. Bioconjug Chem. 2022;33:369–85. https://doi.org/10.1021/acs.bioconjchem.1c00614. source

In the paper

“Ferritin nanocages with MMP-2/9 cleavable anti-PD-L1 peptide and lysosomal pH release of oxaliplatin | MMP-2/9 and lysosomal acidity | HFn displaying anti-PD-L1 peptide via MMP-cleavable linker; oxaliplatin inside | EPR and TfR1-mediated entry; matrix cleavage exposes anti-PD-L1 function; lysosomal pH releases oxaliplatin”

What the sources say

• ?Not checked — no full text of the sourcecites [107] Liu Z, Hao X, Qian J, Zhang H, Bao H, Yang Q, et al. Enzyme/pH dual-responsive engineered nanoparticles for improved tumor immuno-chemotherapy. ACS Appl Mater Interfaces. 2024;16:12951–64. https://doi.org/10.1021/acsami.3c18348. source

In the paper

“A first pulse primes vasculature and stroma, creating a transient window of lower interstitial fluid pressure and higher permeability, after which the transformed carrier exploits the opened paths.”

In the paper

“NIR-II photosensitizer and NO-donor liposomes generate ONOO⁻ in situ, activate MMP-1/2, deplete collagen, increase deposition, and then perform PDT/PTT for tissue-scale penetration in stroma-rich tumors [101].”

What the sources say

• Check pendingcites [101] Li D, Chen X, Dai W, Jin Q, Wang D, Ji J, et al. Photo-triggered cascade therapy: a NIR-II AIE luminogen collaborating with nitric oxide facilitates efficient collagen depletion for boosting pancreatic cancer phototheranostics. Adv Mater. 2024;36:e2306476. https://doi.org/10.1002/adma.202306476. source

In the paper

“Enzymatic ECM degradation and broad MMP activation can loosen structural constraints on tumor and stromal cells, and over-depletion of collagen or hyaluronan has been linked to enhanced invasion, metastatic dissemination and, in some settings, vascular complications [112].”

What the sources say

• Check pendingcites [112] Mayorca-Guiliani AE, Leeming DJ, Henriksen K, Mortensen JH, Nielsen SH, Anstee QM, et al. Ecm formation and degradation during fibrosis, repair, and regeneration. npj Metabolic Health and Disease. 2025;3:25. https://doi.org/10.1038/s44324-025-00063-4. source

In the paper

“acid-induced sphere-to-fiber transitions prolong residence and synchronize dual-drug exposure [106].”

What the sources say

• Check pendingcites [106] Liu Y, Liu Y, Sun X, Wang Y, Du C, Bai J. Morphologically transformable peptide nanocarriers coloaded with doxorubicin and curcumin inhibit the growth and metastasis of hepatocellular carcinoma. Mater Today Bio. 2024;24:100903. https://doi.org/10.1016/j.mtbio.2023.100903. source

In the paper

“A CPP-induced chimera (cpPCC) recruits CRBN to degrade DHHC3 and indirectly destabilize PD-L1; the lead PCC16 achieved DC50 ~ 0.103 μM in C33A cells and reduced tumor weight to 10.1% of the PBS-treated control in ICB-resistant 4T1 xenografts, outperforming BMS-8 (90.8% of control) and a PD-L1 monoclonal antibody (77.9% of control), as well as small-molecule inhibitor [86].”

What the sources say

• Check pendingcites [86] Shi YY, Fan G, Tan R, Li S, Sun HB, Li R, et al. Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates. Cell Death Dis. 2024;15:701. https://doi.org/10.1038/s41419-024-07073-y. source

In the paper

“binding-site barriers and the protein corona can trap carriers near vessels.”

In the paper

“Likewise, tumor-penetrating peptides (e.g., iRGD/CendR pathway) have been broadly used as penetration-promoting modules in peptide-drug conjugates and nanocarriers; when combined with cleavable linkers (e.g., reducible/disulfide or enzyme-responsive motifs), they can improve intratumoral dispersion while helping limit off-target exposure [89].”

What the sources say

• Check pendingcites [89] Yang D, Liu B, Sha H. Advances and prospects of cell-penetrating peptides in tumor immunotherapy. Sci Rep. 2025;15:3392. https://doi.org/10.1038/s41598-025-86130-8. source

In the paper

“Nanozyme-assisted sonodynamic formulations repolarize tumor-associated macrophages to M1 and convert H₂O₂ to O₂ to relieve hypoxia, amplifying low-intensity ultrasound therapy and improving distribution.”

What the sources say

• Check pendingcites [103] Du JR, Teng DK, Wang Y, Wang Q, Lin YQ, Luo Q, et al. Endogenous H2O2 self-replenishment and sustainable cascades enhance the efficacy of sonodynamic therapy. Int J Nanomed. 2023;18:6667–87. https://doi.org/10.2147/IJN.S431221. source

In the paper

“Premature switching can be induced by protein adsorption/corona remodeling, off-target enzymatic cleavage, or heterogeneous pH/redox microdomains, resulting in aggregation, ligand masking, or payload leakage [120]”

What the sources say

• ?Not checked — no full text of the sourcecites [120] Jun T, Weiqing N, Wei L, Rui W, Hui Z, Hongru Z, et al. Smart self-transforming nano-systems for overcoming biological barrier and enhancing tumor treatment efficacy. J Control Release. 2025;380:85–107. https://doi.org/10.1016/j.jconrel.2025.01.058. source

In the paper

“A complementary solution is triggered unmasking: protease-activatable ligands (e.g., uPA-dependent PL3) keep the CendR motif latent during circulation and early vascular contact, then expose it only within the tumor microenvironment, mitigating off-target binding while overcoming the binding-site barrier after extravasation.”

In the paper

“Quantitatively, confocal depth profiling showed that at 100 µm depth the MIP nanocapsules retained ~ 6 × higher fluorescence than the non-imprinted control (CP), whereas CP signals dropped sharply beyond ~ 40–60 µm, indicating more durable deep-layer delivery rather than surface-only accumulation [98].”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Shi J, Wang Y, Wu Y, Li J, Fu C, Li Y, et al. Tumor microenvironment ROS/pH cascade-responsive supramolecular nanoplatform with ROS regeneration property for enhanced hepatocellular carcinoma therapy. ACS Appl Mater Interfaces. 2024;16:7576–92. https://doi.org/10.1021/acsami.3c16022. source

In the paper

“hypoxia-reduced charge-switch micelles achieve transport beyond 400 μm in desmoplastic pancreatic tumor tissue sections and reprogram TGF-β/SMAD stroma [105]”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Zhang S, You H, Fan H, Chen Y, Song H, Zhao Z, et al. Transcytosis-triggering nanoparticles for overcoming stromal barriers and reversing immunosuppression in pancreatic cancer combinatorial therapy. Nano Lett. 2025;25:2949–59. https://doi.org/10.1021/acs.nanolett.4c06372. source

In the paper

“pH- or ROS-only cascades, such as GA-targeted supramolecular nanoparticles, achieve modest size reduction and charge inversion that suffice for improved penetration and efficacy in hepatocellular carcinoma, but their activation strongly depends on the presence of intense oxidative stress and acidity [98].”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Shi J, Wang Y, Wu Y, Li J, Fu C, Li Y, et al. Tumor microenvironment ROS/pH cascade-responsive supramolecular nanoplatform with ROS regeneration property for enhanced hepatocellular carcinoma therapy. ACS Appl Mater Interfaces. 2024;16:7576–92. https://doi.org/10.1021/acsami.3c16022. source

In the paper

“Cross-scale modeling for multistage optimization | Computational parameters and TME hydraulics | Models of vascular, interstitial and cellular transport | Predicts size, charge, IFP and diffusion windows; supports stage-aware design and scheduling”

What the sources say

• ?Not checked — no full text of the sourcecites [108] Jafari-Matanagh S, Razavi SE, Ehghaghi Bonab MB, Omidian H, Omidi Y. Multi-dimensional modeling of nanoparticles transportation from capillary bed into the tumor microenvironment. Comput Biol Med. 2023;152:106477. https://doi.org/10.1016/j.compbiomed.2022.106477. source

In the paper

“Stage-adaptive engineering with RGD gold nanoparticles shows early, looser ECM favors ~ 7 nm carriers via size dominated transport, whereas late, stroma-dense tumors favor larger particles via multivalent αvβ3 interactions, motivating tuning of size, multivalency, and ligand density across disease stages [88].”

What the sources say

• Check pendingcites [88] Nie H, Huang R, Jiang G, Li W, Yang L, Zhang M, et al. Modulating active targeting nanoparticle design according to tumor progressions. Acta Pharm Sin B. 2025;15:1143–58. https://doi.org/10.1016/j.apsb.2024.12.016. source

In the paper

“A remotely boosted catalytic antigen-captured nanosponge further exemplifies ‘multiple interactions’ by coupling marginated accumulation with dual-oxide CDT, field-enhanced ROS generation and antigen transport to program dendritic cells, yielding robust suppression of lung metastases when combined with anti-PD-1 therapy [116].”

What the sources say

• Check pendingcites [116] Chiang MR, Hsu CW, Pan WC, Tran NT, Lee YS, Chiang WH, et al. Reprogramming dysfunctional dendritic cells by a versatile catalytic dual oxide antigen-captured nanosponge for remotely enhancing lung metastasis immunotherapy. ACS Nano. 2025;19:2117–35. https://doi.org/10.1021/acsnano.4c09525. source

In the paper

“Nanozyme-assisted sonodynamic therapy | Low-intensity ultrasound and catalytic O2 | Hyaluronic acid anchored nanozyme for SDT | Long circulation and targeting; ultrasound triggers SDT; nanozyme converts H2O2 to O2 to relieve hypoxia; macrophage repolarization to M1”

What the sources say

• Check pendingcites [103] Du JR, Teng DK, Wang Y, Wang Q, Lin YQ, Luo Q, et al. Endogenous H2O2 self-replenishment and sustainable cascades enhance the efficacy of sonodynamic therapy. Int J Nanomed. 2023;18:6667–87. https://doi.org/10.2147/IJN.S431221. source

In the paper

“Consistent with this, ex vivo organ/tumor fluorescence quantification showed higher tumor-associated signal for the nanoparticle group (tumor ~ 21.0%) while free DOX distributed predominantly to off-target organs (e.g., liver, kidney, lung), providing a second quantitative proxy for more tumor-localized exposure.”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Hu L, Xiong C, Wei G, Yu Y, Li S, Xiong X, et al. Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer. J Colloid Interface Sci. 2022;608:1882–93. https://doi.org/10.1016/j.jcis.2021.10.070. source

In the paper

“Hypoxia-reduced charge-switch micelles that trigger transcytosis | Hypoxia and low pH | N-oxide based micelles with CBP decoration; gemcitabine derivative and galunisertib | Stealth during circulation; reduction to tertiary amines switches charge; activation of transcytosis; TGF-β/SMAD stroma remodeling”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Zhang S, You H, Fan H, Chen Y, Song H, Zhao Z, et al. Transcytosis-triggering nanoparticles for overcoming stromal barriers and reversing immunosuppression in pancreatic cancer combinatorial therapy. Nano Lett. 2025;25:2949–59. https://doi.org/10.1021/acs.nanolett.4c06372. source

In the paper

“Enzyme and pH orthogonality can first shed HA or MMP-2 cleavable coats to contract particles from roughly 150 nm to about 50 nm, then trigger pH-guided doxorubicin release under CD44 recognition [96].”

What the sources say

• ?Not checked — no full text of the sourcecites [96] Dai W, Zhou X, Zhao J, Lei L, Huang Y, Jia F, et al. Tumor microenvironment-modulated nanoparticles with cascade energy transfer as internal light sources for photodynamic therapy of deep-seated tumors. Biomaterials. 2025;312:122743. https://doi.org/10.1016/j.biomaterials.2024.122743. source

In the paper

“MOF@poly(ortho ester) core–shell nanocomposite | Acidic pH | MOF core with acid-labile poly(ortho ester) shell; doxorubicin or cisplatin | Blood stability with negative surface; shell loss in TME exposes positive core; nuclear-proximal delivery”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Hu L, Xiong C, Wei G, Yu Y, Li S, Xiong X, et al. Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer. J Colloid Interface Sci. 2022;608:1882–93. https://doi.org/10.1016/j.jcis.2021.10.070. source

In the paper

“GSH-responsive paclitaxel-IR780 platforms use photothermal priming to raise permeability and then rely on redox conditions for intracellular release, yielding chemo-PTT synergy [102].”

What the sources say

• ?Not checked — no full text of the sourcecites [102] Dai Q, Du Z, Jing L, Zhang R, Tang W. Enzyme-responsive modular peptides enhance tumor penetration of quantum dots via charge reversal strategy. ACS Appl Mater Interfaces. 2024;16:6208–20. https://doi.org/10.1021/acsami.3c11500. source

In the paper

“Representative multi-interaction designs have demonstrated marked therapeutic impact in hypovascular metastases by integrating organ-selective targeting/charge conversion with catalytic stress, endo/lysosomal escape and antigen capture, thereby enhancing PD-L1 gene silencing and sustained DC/T-cell activation [109].”

What the sources say

• Check pendingcites [109] Huynh TMH, Huang PX, Wang KL, Tran NT, Iao HM, Pan WC, et al. Reprogramming immunodeficiency in lung metastases via PD-L1 siRNA delivery and antigen capture of nanosponge-mediated dendritic cell modulation. ACS Nano. 2025;19:25134–53. https://doi.org/10.1021/acsnano.5c05395. source

In the paper

“Platelet-mimicking coatings and platelet membrane cloaks improve homing and retention, but they also intersect with coagulation pathways and may, in principle, increase the risk of microthrombosis or coagulation abnormalities if not carefully dosed and monitored [113].”

What the sources say

• ?Not checked — no full text of the sourcecites [113] Qinyi Z, Qiuhua L, Zimeng L, Mengchi S, Xiao D. Nano-ROS-generating approaches to cancer dynamic therapy: lessons from nanoparticles. Chem Eng J. 2023;457:141225. https://doi.org/10.1016/j.cej.2022.141225. source

In the paper

“NIR-II AIE luminogen with NO-donor liposomes (Lip-DTI/NO) | NIR light and NO; peroxynitrite cascade | Liposomes with NIR-II AIEgen and SNAP NO donor | Photo-driven O2•- and heat; NO release; ONOO − activation of MMPs; collagen depletion creates a window for penetration; imaging and therapy combined”

What the sources say

• Check pendingcites [101] Li D, Chen X, Dai W, Jin Q, Wang D, Ji J, et al. Photo-triggered cascade therapy: a NIR-II AIE luminogen collaborating with nitric oxide facilitates efficient collagen depletion for boosting pancreatic cancer phototheranostics. Adv Mater. 2024;36:e2306476. https://doi.org/10.1002/adma.202306476. source

In the paper

“In this “affinity penetration paradox,” maximizing binding strength does not necessarily maximize tumor coverage; instead, it can suppress the very trans-tissue transport that CendR programs are intended to enable [92].”

What the sources say

• Check pendingcites [92] Xu Y, Yang S, Rao Q, Gao Y, Zhou G, Zhao D, et al. A mechanistic quantitative systems pharmacology model platform for translational efficacy evaluation and checkpoint combination design of bispecific immuno-modulatory antibodies. Front Pharmacol. 2025;16:1571844. https://doi.org/10.3389/fphar.2025.1571844. source

In the paper

“Dual pH/GSH micelles combine charge reversal with disulfide cleavage to co-deliver siPD-L1 and indocyanine green, aligning photothermal guidance with checkpoint silencing [24].”

What the sources say

• ?Not checked — no full text of the sourcecites [24] Ma T, Li W, Ye J, Huang C, Li Y, Qiu H, et al. GSH/pH dual response drug delivery system for photothermal enhanced gene-immunotherapy. Nanoscale. 2023;15:16947–58. https://doi.org/10.1039/d3nr03881e. source

In the paper

“Otherwise, additional stages tend to increase CMC burden faster than they improve patient relevant performance.”

In the paper

“Ligand and CendR or transcytosis systems are likewise high priority when they are designed to overcome binding site barriers through moderated avidity or protease or redox gated exposure.”

In the paper

“In summary, the field is moving from smarter materials to transport programmed systems.”

In the paper

“Designs that target the dominant barrier for a given tumor phenotype, execute a short and verifiable activation sequence, and deliver distribution gains without disproportionate CMC burden are most likely to convert strong preclinical penetration into consistent and patient relevant benefit.”

In the paper

“Tumor penetration is fundamentally a transport problem embedded in a heterogeneous and dynamically evolving microenvironment.”

In the paper

“Barrier priming approaches that transiently normalize perfusion or decompress stroma are high leverage because they act upstream on dominant transport bottlenecks and can benefit multiple payload classes.”