Recent Advances and Challenges in Gene Delivery Mediated by Polyester-Based Nanoparticles

Figures & data

Figure 1 Delivery of different nucleic acids (DNA, mRNA, miRNA or siRNA) by non-viral vectors based on polyester NPs. The image represents the cell interaction and uptake, via endocytosis, of polyester-based NPs delivering NA. After endocytosis and endosomal escape, NA are released by the NPs and they follow different specific pathways. siRNA and miRNA act by binding the RNA-induced silencing complex (RISC), mRNA bind the translational machinery (ribosome) to be translated, and DNA must be transported to the nucleus to exert its activity. In the inset, the chemical structures of PLGA and PLA are reported.

Figure 2 Schematic illustration of the structure and chemical components of multifunctional PBAE-PLGA-Ag₂S-RA-siSOX9 (PPAR-siSOX9) nanoformulation.

Notes: Reproduced with permission from Huang D, Cao Y, Yang X et al. A Nanoformulation-Mediated Multifunctional Stem Cell Therapy with Improved Beta-Amyloid Clearance and Neural Regeneration for Alzheimer’s Disease. Adv Mater. 2021;33:2006357. © 2021 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim under Creative Commons Attribution 4.0 International License.⁷⁵

Figure 3 Schematic illustration of CLAN encapsulating mRNA coding for the model immunology protein OVA that stimulates the maturation of DCs, promotes the activation and proliferation of antigen-specific T cells and induces a robust anti-tumor immune response in an aggressive E.G7-OVA lymphoma murine model.

Notes: Reprinted with permission from Fan YN, Li M, Luo YL, et al. Cationic lipid-assisted nanoparticles for delivery of mRNA cancer vaccine. Biomater Sci. 2018;6:3009–3018;⁸⁶ permission conveyed through Copyright Clearance Center, Inc.

Figure 4 Schematic illustration of the effects of the folate targeted gene-delivery system consisting of methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and DOTAP loaded with CCL19 (FA-DMA/CCL19). The gene delivered into tumor cells expresses and secrets CCL19 protein factor, which induced activation of the immune system to kill cancer.

Notes: Reprinted with permission from Liu X, Wang B, Li Y, et al. Powerful Anticolon Tumor Effect of Targeted Gene Immunotherapy Using Folate-Modified Nanoparticle Delivery of CCL19 To Activate the Immune System. ACS Cent Sci. 2019;5:277–289 (https://pubs.acs.org/doi/10.1021/acscentsci.8b00688).⁹⁵ Copyright (2019) American Chemical Society. Further permissions related to the material excerpted should be directed to the ACS.

Figure 5 Schematic representation of different configurations of Cas9/sgRNA elements used in the intracellular delivery: format a delivers plasmid DNA encoding Cas9 proteins and sgRNA; format b delivers mRNA and sgRNA; format c delivers Cas9 protein complexed with sgRNA (ribonucleoprotein RNP).

Figure 6 (A) Schematic representation of Cationic Lipid Assisted Nanoparticles (CLAN) preparation by double emulsion solvent evaporation method. (B) CLAN vector and its components (PEG_5K-PLGA_11K, cationic BHEM-Chol lipid, and plasmid); (C) Representative TEM image of CLAN_pM458.

Notes: Panels B and C reprinted with permission from Luo YL, Xu CF, Li HJ, et al. Macrophage-Specific in Vivo Gene Editing Using Cationic Lipid-Assisted Polymeric Nanoparticles. ACS Nano. 2018;12:994–1005.⁸⁵ Copyright (2018) American Chemical Society.

Table 1 Overview of COVID-19 Vaccines Licensed or Under Development

Vaccine Target	Name	Delivery System/Formulation	Status
Inactivated virus vaccines, which use inactivated or weakened virus to generate an immune response without disease	PiCoVacc	Inactivated SARS-CoV-2 + alum adjuvant	Clinical trial ongoing
	Sinovac (Sinovac and Instituto Butatan) (known as CoronaVac)	Inactivated SARS-CoV-2 + alum adjuvant	Approved in China and Bahrain. Emergency use in other countries
	Sinopharm (BBIBP-CorV)	Inactivated virus produced in Vero cells	Approved in China. Emergency use in other countries
Vaccines Based on Full-Length S Protein to generate an immune response	Novavax (NVX-CoV2373)	Spontaneous NPs formation; it contains a saponine-based adjuvant	Under review by EMA and FDA
Protein Subunit Vaccine (RBD-Based vaccine) RBD of SARS-CoV-S contains major antigenic epitopes	NCT 04473690 (Kentucky Bioprocessing Inc.)	Recombinant antigenic proteins that induce both neutralizing antibodies and T cell responses	I and II clinical trials (NCT04473690)
Viral vector vaccines, which use non-replicating viral vector as platform to produce coronavirus proteins to generate an immune response	Vaxzevria Oxford/AstraZeneca (AZD1222)	Chimpanzee Ad (ChAdOx1) expressing the gene of S protein	Approved in Brazil. Emergency use in the UK, EU, other countries. Stopped use in Denmark.
	Gam-COVID-Vac (Sputnik V)	Modified Ad26 and Ad5 viruses containing the gene for S protein	Approved in Russia; under review by EMA
	Janssen (Johnson & Johnson) (JNJ-78436735)	Recombinant, replication-incompetent Ad26 expressing the S protein	FDA/ EMA approved
	Ad5-nCoV CanSinoBio	Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector)
RNA vaccines: is a cutting-edge approach that uses genetically engineered RNA to generate a protein that itself safely prompts an immune response	Comirnaty (BioNTech/Pfizer)	Lipid NPs	FDA/ EMA approved
	Moderna	Lipid NPs	FDA/ EMA approved
	CureVac (CVnCoV vaccine)	Lipid NPs	Results of phase 2b/3 (June 2021) indicated an efficacy of 47% in symptomatic disease, lower than 50% and 70% efficacy requested by the FDA and OMS, respectively.^Citation130,^Citation131
DNA vaccines which use plasmid DNA to generate a protein that prompts an immune response	AG0301-COVID19 (AnGesInc)	Plasmid encoding S protein	Phase 1/2
	INO-4800 (Inovio Pharmaceuticals)	DNA with electroporation	Phase 2–3 (USA) (NCT04642638)

Huang D, Cao Y, Yang X, et al. A nanoformulation-mediated multifunctional stem cell therapy with improved beta-amyloid clearance and neural regeneration for alzheimer’s disease. Adv Mater. 2021;33:2006357. doi:10.1002/adma.202006357

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Fan YN, Li M, Luo YL, et al. Cationic lipid-assisted nanoparticles for delivery of mRNA cancer vaccine. Biomater Sci. 2018;6:3009–3018. doi:10.1039/C8BM00908B

 PubMed Web of Science ®Google Scholar

Liu X, Wang B, Li Y, et al. Powerful anticolon tumor effect of targeted gene immunotherapy using folate-modified nanoparticle delivery of CCL19 to activate the immune system. ACS Cent Sci. 2019;5:277–289. doi:10.1021/acscentsci.8b00688

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Luo YL, Xu CF, Li HJ, et al. Macrophage-specific in vivo gene editing using cationic lipid-assisted polymeric nanoparticles. ACS Nano. 2018;12:994–1005. doi:10.1021/acsnano.7b07874

 PubMed Web of Science ®Google Scholar

Burger L. Healthcare & Pharmaceuticals. CureVac fails in pivotal COVID-19 vaccine trial with 47% efficacy. Available from: https://www.reuters.com/business/healthcare-pharmaceuticals/curevacs-covid-19-vaccine-misses-efficacy-goal-mass-trial-2021-06-16. Accessed August 12, 2021.

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CureVac Provides Update on Phase 2b/3 Trial of First-Generation COVID-19 Vaccine Candidate, CVnCoV (press release). Available from: https://www.curevac.com/en/2021/06/16/curevac-provides-update-on-phase-2b-3-trial-of-first-generation-covid-19-vaccine-candidate-cvncov/. Accessed August 12, 2021.

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