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Multifunctional elastin-like polypeptide nanocarriers for efficient miRNA delivery in cancer therapy

Hong, Jisan, Sim, Dahye, Lee, Byung-Heon, Sarangthem, Vijaya, Park, Rang-Woon·2024·Journal of Nanobiotechnology
DOI 10.1186/s12951-024-02559-5PMC PMC11131307
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Abstract

Background: The exogenous delivery of miRNA to mimic and restore miRNA-34a activity in various cancer models holds significant promise in cancer treatment. Nevertheless, its effectiveness is often impeded by challenges, including a short half-life, propensity for off-target accumulation, susceptibility to inactivation by blood-based enzymes, concerns regarding patient safety, and the substantial cost associated with scaling up. As a means of overcoming these barriers, we propose the development of miRNA-loaded Tat-A86 nanoparticles by virtue of Tat-A86's ability to shield the loaded agent from external environmental factors, reducing degradation and inactivation, while enhancing circulation time and targeted accumulation. Results: Genetically engineered Tat-A86, featuring 16 copies of the interleukin-4 receptor (IL-4R)-binding peptide (AP1), Tat for tumor penetration, and an elastin-like polypeptide (ELP) for presenting target ligands and ensuring stability, served as the basis for this delivery system. Comparative groups, including Tat-E60 and A86, were employed to discern differences in binding and penetration. The designed ELP-based nanoparticle Tat-A86 effectively condensed miRNA, forming stable nanocomplexes under physiological conditions. The miRNA/Tat-A86 formulation bound specifically to tumor cells and facilitated stable miRNA delivery into them, effectively inhibiting tumor growth. The efficacy of miRNA/Tat-A86 was further evaluated using three-dimensional spheroids of lewis lung carcinoma (LLC) as in vitro model and LLC tumor-bearing mice as an in vivo model. It was found that miRNA/Tat-A86 facilitates effective cell killing by markedly improving miRNA penetration, leading to a substantial reduction in the size of LLC spheroids. Compared to other controls, Tat-A86 demonstrated superior efficacy in suppressing the growth of 3D cellular aggregates. Moreover, at equivalent doses, miRNA-34a delivered by Tat-A86 inhibited the growth of LLC cells in allograft mice. Conclusions: Overall, these studies demonstrate that Tat-A86 nanoparticles can deliver miRNA systemically, overcoming the basic hurdles impeding miRNA delivery by facilitating both miRNA uptake and stability, ultimately leading to improved therapeutic effects. Graphical Abstract:

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Figures

Fig. 1 Design and expression of miRNA-binding ELPs. a Schematic representation of chimeric fusion ELPs encoding A86, Tat-E60, and Tat-A86, along with their corresponding amino acid sequences. b The carrier component of the ELP fusion protein is pivotal in mediating the interaction with miRNA. The positively charged amino acids in ELPs induce complexation with the negatively charged nucleic acids to form stable nano complexes. c pET 25b + vectors harboring Tat-E60, A86, and Tat-A86 genes were individually transformed into the Escherichia coli strain BL21 for ELP protein expression. Purification of all fusion ELPs involved triggering a phase transition and a repeated cycle of hot spin to aggregate protein, followed by cold spin to dissolve the ELP pellet, continued for four rounds to achieve homogeneity in fusion ELPs from cell lysate. The size and purity of the purified fusion proteins were confirmed through sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE), and Coomassie blue staining was employed for visualization. The size of each fusion ELP is indicated below the gel image
Fig. 1 Design and expression of miRNA-binding ELPs. a Schematic representation of chimeric fusion ELPs encoding A86, Tat-E60, and Tat-A86, along with their corresponding amino acid sequences. b The carrier component of the ELP fusion protein is pivotal in mediating the interaction with miRNA. The positively charged amino acids in ELPs induce complexation with the negatively charged nucleic acids to form stable nano complexes. c pET 25b + vectors harboring Tat-E60, A86, and Tat-A86 genes were individually transformed into the Escherichia coli strain BL21 for ELP protein expression. Purification of all fusion ELPs involved triggering a phase transition and a repeated cycle of hot spin to aggregate protein, followed by cold spin to dissolve the ELP pellet, continued for four rounds to achieve homogeneity in fusion ELPs from cell lysate. The size and purity of the purified fusion proteins were confirmed through sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE), and Coomassie blue staining was employed for visualization. The size of each fusion ELP is indicated below the gel imageCC BY · PubMed Central
Fig. 2 The binding of ELPs to LLC and 4T1 cells. LLC (a) and 4T1 (b) cells were incubated with fluorescein isothiocyanate (FITC)-labelled ELPs (0.5 µM) at 37 °C for 1 h. The percentage of cell-binding was analyzed through flow cytometry (n = 3). Graphical bars on the right represent the percentage of ELP-bound cells as the mean ± standard deviation (SD) of data obtained from three separate experiments performed in triplicate. ***P < 0.001 (one-way analysis of variance (ANOVA)) indicates significant differences for Tat-E60, A86 and Tat-A86 compared with untreated control. c LLC cells were treated with 0.5 µM of the respective fluorescein isothiocyanate (FITC)-labelled polypeptides at 37 °C for 1 h and observed under confocal laser microscopy. Cell membranes and nuclei were stained with Wheat Germ Agglutinin Alexa 594 and Hoechst, respectively. Representative confocal images from five independent experiments. Scale bar, 20 µm
Fig. 2 The binding of ELPs to LLC and 4T1 cells. LLC (a) and 4T1 (b) cells were incubated with fluorescein isothiocyanate (FITC)-labelled ELPs (0.5 µM) at 37 °C for 1 h. The percentage of cell-binding was analyzed through flow cytometry (n = 3). Graphical bars on the right represent the percentage of ELP-bound cells as the mean ± standard deviation (SD) of data obtained from three separate experiments performed in triplicate. ***P < 0.001 (one-way analysis of variance (ANOVA)) indicates significant differences for Tat-E60, A86 and Tat-A86 compared with untreated control. c LLC cells were treated with 0.5 µM of the respective fluorescein isothiocyanate (FITC)-labelled polypeptides at 37 °C for 1 h and observed under confocal laser microscopy. Cell membranes and nuclei were stained with Wheat Germ Agglutinin Alexa 594 and Hoechst, respectively. Representative confocal images from five independent experiments. Scale bar, 20 µmCC BY · PubMed Central
Fig. 3 Gel retardation assay of miRNA/ELP complexes. a The complexation of Tat-E60, A86, and Tat-A86 with miRNA was examined at different miRNA/ELP ratios. Interactions between miRNA (10 μM) and ELPs (10–200 μM) were assessed using a gel retardation assay. The gels were visualized by staining with ethidium bromide. Lane 1: 1 kb DNA ladder, Lane 2: naked miRNA (22 bp), Lanes 3–7: miRNA/ELP complexes at different molar ratios. b The stability of encapsulated miRNA was evaluated by subjecting miRNA/ELP complexes to treatment with or without RNase A for 1 h. The samples were loaded alongside naked miRNA (Lane 2) and in the presence of RNase I (Lane 3). Lanes 5, 8, and 11 depict untreated Tat-E60/miRNA, Tat-A86/miRNA and A86/miRNA complexes, respectively. Lanes 6, 9, and 12 depict RNase A-treated Tat-E60/miRNA, Tat-A86/miRNA and A86/miRNA complexes respectively. Electrophoresis was performed on a 1% agarose gel in tris–acetate-EDTA (TAE) buffer, and gel visualization was achieved by staining with ethidium bromide. c A naked miRNA (Lane 2) or miRNA/ELPs complexes (Lane 3–5) were incubated with the 50% mouse serum for 24 h. Following incubation, the miRNA was liberated from the complexes utilizing heparin and subsequently subjected to analysis via agarose gel electrophoresis
Fig. 3 Gel retardation assay of miRNA/ELP complexes. a The complexation of Tat-E60, A86, and Tat-A86 with miRNA was examined at different miRNA/ELP ratios. Interactions between miRNA (10 μM) and ELPs (10–200 μM) were assessed using a gel retardation assay. The gels were visualized by staining with ethidium bromide. Lane 1: 1 kb DNA ladder, Lane 2: naked miRNA (22 bp), Lanes 3–7: miRNA/ELP complexes at different molar ratios. b The stability of encapsulated miRNA was evaluated by subjecting miRNA/ELP complexes to treatment with or without RNase A for 1 h. The samples were loaded alongside naked miRNA (Lane 2) and in the presence of RNase I (Lane 3). Lanes 5, 8, and 11 depict untreated Tat-E60/miRNA, Tat-A86/miRNA and A86/miRNA complexes, respectively. Lanes 6, 9, and 12 depict RNase A-treated Tat-E60/miRNA, Tat-A86/miRNA and A86/miRNA complexes respectively. Electrophoresis was performed on a 1% agarose gel in tris–acetate-EDTA (TAE) buffer, and gel visualization was achieved by staining with ethidium bromide. c A naked miRNA (Lane 2) or miRNA/ELPs complexes (Lane 3–5) were incubated with the 50% mouse serum for 24 h. Following incubation, the miRNA was liberated from the complexes utilizing heparin and subsequently subjected to analysis via agarose gel electrophoresisCC BY · PubMed Central
Fig. 4 Physical characterization of miRNA/ELP complexes. a The turbidity profiles of the miRNA/ELP complexes (red) were assessed at 350 nm, with a temperature increase of 1 °C/min, and compared with those of naïve ELPs (black) at various temperatures. To validate the stable condensation of miRNA/ELP complexes, nanoparticle size was determined using dynamic light scattering (DLS) at 24 °C. The size parameters of ELPs alone and sizes following complex formation including Tat-E60 (b, c), A86 (d, e), and Tat-A86 (f, g) were evaluated. h TEM images of miRNA/Tat-E60, miRNA/A86 and miRNA/Tat-A86 nanocomplexes at room temperature. Scale bar = 200 nm
Fig. 4 Physical characterization of miRNA/ELP complexes. a The turbidity profiles of the miRNA/ELP complexes (red) were assessed at 350 nm, with a temperature increase of 1 °C/min, and compared with those of naïve ELPs (black) at various temperatures. To validate the stable condensation of miRNA/ELP complexes, nanoparticle size was determined using dynamic light scattering (DLS) at 24 °C. The size parameters of ELPs alone and sizes following complex formation including Tat-E60 (b, c), A86 (d, e), and Tat-A86 (f, g) were evaluated. h TEM images of miRNA/Tat-E60, miRNA/A86 and miRNA/Tat-A86 nanocomplexes at room temperature. Scale bar = 200 nmCC BY · PubMed Central
Fig. 5 Cellular uptake and intracellular tracking of miRNA/ELP complexes. Uptake of FAM-labeled miRNA/ELP complexes by LLC (a) and 4T1 (b) cells was investigated. LLC and 4T1 cells were individually mixed with the complexes and incubated at 37 °C for 1 h. Subsequently, the miRNA uptake percentages were determined using flow cytometry (n = 3). Graphical bars on the right illustrate the mean ± SD of miRNA uptake percentages, derived from three independent experiments conducted in triplicate. ***P < 0.001, one-way analysis of variance (ANOVA) indicates significant differences for Tat-E60, A86 and Tat-A86 complexes compared with untreated control. c LLC cells were incubated with miRNA/ELP complexes containing 150 pmol of FAM-labeled miRNA for 1 h and 4 h. Lysosomal compartments were selectively labeled using LysoTracker Red DND-99, and the dynamic subcellular localization of miRNA was examined in real-time using a Zeiss confocal microscope. The yellow signal depicts the co-localization of miRNA with the lysosomal marker. Representative confocal microscopic images from five experiments (n = 5) are presented, with blue indicating nuclei stained with Hoechst, green representing miRNA/ELP complexes, and red corresponding to LysoTracker. Scale bar, 10 µm
Fig. 5 Cellular uptake and intracellular tracking of miRNA/ELP complexes. Uptake of FAM-labeled miRNA/ELP complexes by LLC (a) and 4T1 (b) cells was investigated. LLC and 4T1 cells were individually mixed with the complexes and incubated at 37 °C for 1 h. Subsequently, the miRNA uptake percentages were determined using flow cytometry (n = 3). Graphical bars on the right illustrate the mean ± SD of miRNA uptake percentages, derived from three independent experiments conducted in triplicate. ***P < 0.001, one-way analysis of variance (ANOVA) indicates significant differences for Tat-E60, A86 and Tat-A86 complexes compared with untreated control. c LLC cells were incubated with miRNA/ELP complexes containing 150 pmol of FAM-labeled miRNA for 1 h and 4 h. Lysosomal compartments were selectively labeled using LysoTracker Red DND-99, and the dynamic subcellular localization of miRNA was examined in real-time using a Zeiss confocal microscope. The yellow signal depicts the co-localization of miRNA with the lysosomal marker. Representative confocal microscopic images from five experiments (n = 5) are presented, with blue indicating nuclei stained with Hoechst, green representing miRNA/ELP complexes, and red corresponding to LysoTracker. Scale bar, 10 µmCC BY · PubMed Central
Fig. 6 Cell viability assay. The impact of miRNA-34a on the growth of LLC (a, b) and 4T1 (c, d) cells was assessed following transfection with miRNA/ELPs. LLC or 4T1 cells (5 × 103/well) in a 96-well plate were treated with negative control (NC) miRNA/ELPs and miRNA-34a/ELPs at concentrations ranging from 50 to 400 nM for 48 h. Cell proliferation was evaluated using a CCK assay. Specifically, 10 μL of CCK-8 solution was added to each well and incubated for 1 h at 37 ℃, and the change in absorbance was measured at a wavelength of 450 nm. One-way ANOVA was performed to assess the statistical significance of the differences among groups treated with miRNA/ELP complexes at different miRNA concentrations. *P < 0.05, NC miRNA/A86 vs. miRNA-34a/A86 (400 nM) delivery, and **P < 0.001, NC miRNA/Tat-A86 vs. miRNA-34a/Tat-A86-mediated miRNA (400 nM) delivery
Fig. 6 Cell viability assay. The impact of miRNA-34a on the growth of LLC (a, b) and 4T1 (c, d) cells was assessed following transfection with miRNA/ELPs. LLC or 4T1 cells (5 × 103/well) in a 96-well plate were treated with negative control (NC) miRNA/ELPs and miRNA-34a/ELPs at concentrations ranging from 50 to 400 nM for 48 h. Cell proliferation was evaluated using a CCK assay. Specifically, 10 μL of CCK-8 solution was added to each well and incubated for 1 h at 37 ℃, and the change in absorbance was measured at a wavelength of 450 nm. One-way ANOVA was performed to assess the statistical significance of the differences among groups treated with miRNA/ELP complexes at different miRNA concentrations. *P < 0.05, NC miRNA/A86 vs. miRNA-34a/A86 (400 nM) delivery, and **P < 0.001, NC miRNA/Tat-A86 vs. miRNA-34a/Tat-A86-mediated miRNA (400 nM) deliveryCC BY · PubMed Central
Fig. 7 miR-34a/ELPs induce G2/M phase arrest and cellular apoptosis. a LLC cells were transfected with miRNA-34a/ ELP, and the cell cycle distribution was analyzed 48 h post-transfection using flow cytometry after propidium iodide (PI) staining. b Flow cytometry analysis, followed by annexin V–PI staining, revealed the apoptosis percentages in LLC cells treated with different miRNA-34a/ELPs. Representative images from the flow cytometry analysis are shown. c The percentages of cell populations in the G0/G1, S, and G2/M phases were analyzed relative to the total phases. Most miRNA-34a/ELPs induced cell cycle arrest at the G2/M phase in LLC cells. Data are presented as the mean ± SD from at least three independent experiments. ***P < 0.001 indicates statistically significant difference in the miR-34a/Tat-E60, miR-34a/A86 and miR-34a/Tat-A86 -treated group compared to the control group. d The percentage of apoptotic cells increased significantly in miRNA-34a/Tat-A86-treated LLC cells compared to the control. Data are presented as the mean ± SD for relative apoptosis normalized to control cells for three independent experiments. Columns represent the mean of three separate experiments, while bars represent the SD. **P < 0.01, ***P < 0.001 as determined by ANOVA test, miRNA-34a/Tat-E60 vs. miRNA/miRNA-34a/A86, and miRNA-34a/Tat-E60 vs. miRNA-34a/Tat-A86
Fig. 7 miR-34a/ELPs induce G2/M phase arrest and cellular apoptosis. a LLC cells were transfected with miRNA-34a/ ELP, and the cell cycle distribution was analyzed 48 h post-transfection using flow cytometry after propidium iodide (PI) staining. b Flow cytometry analysis, followed by annexin V–PI staining, revealed the apoptosis percentages in LLC cells treated with different miRNA-34a/ELPs. Representative images from the flow cytometry analysis are shown. c The percentages of cell populations in the G0/G1, S, and G2/M phases were analyzed relative to the total phases. Most miRNA-34a/ELPs induced cell cycle arrest at the G2/M phase in LLC cells. Data are presented as the mean ± SD from at least three independent experiments. ***P < 0.001 indicates statistically significant difference in the miR-34a/Tat-E60, miR-34a/A86 and miR-34a/Tat-A86 -treated group compared to the control group. d The percentage of apoptotic cells increased significantly in miRNA-34a/Tat-A86-treated LLC cells compared to the control. Data are presented as the mean ± SD for relative apoptosis normalized to control cells for three independent experiments. Columns represent the mean of three separate experiments, while bars represent the SD. **P < 0.01, ***P < 0.001 as determined by ANOVA test, miRNA-34a/Tat-E60 vs. miRNA/miRNA-34a/A86, and miRNA-34a/Tat-E60 vs. miRNA-34a/Tat-A86CC BY · PubMed Central
Fig. 8 Growth inhibition assay using the LLC spheroids. a–d LLC spheroids were treated with different miRNA/ELP complexes, featuring varying miRNA-34a concentrations (5 or 10 μM) encapsulated within different ELPs. The time-dependent increase in the diameter of LLC spheroids was monitored for 10 days using bright-field imaging. Representative images of spheroid treated with miRNA/ELP complexes are presented. LLC spheroids cultured in Roswell Park Memorial Institute (RPMI) medium served as a control. Scale bar, 500 μm. Growth curve of LLC spheroids after various treatments. **P < 0.01, Tat-A86/miRNA-34a treated vs. control group from day 6 onwards. e, f Cell viability assay of the differently sized spheroids (day 3 and day 6) using live/dead staining with ethidium homodimer-1 and calcein AM. Viable cells are depicted in green, while nonviable cells are shown in red. Scale bar, 500 μm
Fig. 8 Growth inhibition assay using the LLC spheroids. a–d LLC spheroids were treated with different miRNA/ELP complexes, featuring varying miRNA-34a concentrations (5 or 10 μM) encapsulated within different ELPs. The time-dependent increase in the diameter of LLC spheroids was monitored for 10 days using bright-field imaging. Representative images of spheroid treated with miRNA/ELP complexes are presented. LLC spheroids cultured in Roswell Park Memorial Institute (RPMI) medium served as a control. Scale bar, 500 μm. Growth curve of LLC spheroids after various treatments. **P < 0.01, Tat-A86/miRNA-34a treated vs. control group from day 6 onwards. e, f Cell viability assay of the differently sized spheroids (day 3 and day 6) using live/dead staining with ethidium homodimer-1 and calcein AM. Viable cells are depicted in green, while nonviable cells are shown in red. Scale bar, 500 μmCC BY · PubMed Central
Fig. 9 The antitumor effect of miRNA-34a/ELPs in vivo. a LLC allograft mice were randomly divided into five groups and administered intravenous injections of either free miRNA-34a (6 mg/kg) or miRNA-34a/ELPs (6 mg/kg on days 1, 3, 6, 8, and 10). Tumor volumes (mm3) were monitored every after 3 days for 20 days. b Tumor volumes are presented as mean ± SD (n = 5 per group). c The average body weight of each group is expressed as the mean ± SD (n = 5 per group). d Tumors in each group, including the control (PBS), free miRNA-34a, Tat-E60, A86, and Tat-A86 groups, were excised and photographed after 20 days. e Average tumor weight in each group at the end of the experiments. Columns represent the mean for three replicate determinations, while bars indicate SD. ***P < 0.001 indicates the statistically significant difference in the miRNA-34a/Tat-A86-treated group compared to the control PBS group
Fig. 9 The antitumor effect of miRNA-34a/ELPs in vivo. a LLC allograft mice were randomly divided into five groups and administered intravenous injections of either free miRNA-34a (6 mg/kg) or miRNA-34a/ELPs (6 mg/kg on days 1, 3, 6, 8, and 10). Tumor volumes (mm3) were monitored every after 3 days for 20 days. b Tumor volumes are presented as mean ± SD (n = 5 per group). c The average body weight of each group is expressed as the mean ± SD (n = 5 per group). d Tumors in each group, including the control (PBS), free miRNA-34a, Tat-E60, A86, and Tat-A86 groups, were excised and photographed after 20 days. e Average tumor weight in each group at the end of the experiments. Columns represent the mean for three replicate determinations, while bars indicate SD. ***P < 0.001 indicates the statistically significant difference in the miRNA-34a/Tat-A86-treated group compared to the control PBS groupCC BY · PubMed Central
Fig. 10 Ex vivo histological analyses based on hematoxylin and eosin (H&E) staining. Following the treatment regimen, tumor sections were excised from the LCC tumor-bearing mice. Nuclei are stained in blue, while the extracellular matrix and cytoplasm are stained in red using H&E staining. Scale bar, 50 μm
Fig. 10 Ex vivo histological analyses based on hematoxylin and eosin (H&E) staining. Following the treatment regimen, tumor sections were excised from the LCC tumor-bearing mice. Nuclei are stained in blue, while the extracellular matrix and cytoplasm are stained in red using H&E staining. Scale bar, 50 μmCC BY · PubMed Central
Fig. 11 Analysis of apoptosis based on terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Apoptosis in tumor tissues across various groups (n = 5) was assessed through TUNEL staining. Apoptotic cells are represented by green spots, while intact DNA is marked in blue stain using DAPI. Scale bar, 50 µm
Fig. 11 Analysis of apoptosis based on terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Apoptosis in tumor tissues across various groups (n = 5) was assessed through TUNEL staining. Apoptotic cells are represented by green spots, while intact DNA is marked in blue stain using DAPI. Scale bar, 50 µmCC BY · PubMed Central

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Metadata

Authors
Hong, J., Sim, D., Lee, B.-H., Sarangthem, V., & Park, R.-W.
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2024-05-27
Volume
22
Issue
1
ISSN
1477-3155
DOI
10.1186/s12951-024-02559-5
PMC
PMC11131307
Cited by
22
References
1
Language
en
Licence
Funders
  • National Research Foundation of Korea (2021R1A5A2021614)
  • Brain Korea 21(BK21), Republic of Korea (4199990714163)

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