Recent Advances in Non-Viral Vectors for Gene Therapy and Gene Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: 31 October 2026 | Viewed by 5359

Special Issue Editor

Special Issue Information

Dear Colleagues,

We are pleased to invite submissions to this Special Issue, entitled “Recent Advances in Non-Viral Vectors for Gene Therapy and Gene Delivery”. Non-viral platforms have progressed from exploratory formulations to clinically validated vehicles for mRNA and siRNA, while the efficient, tissue-selective delivery of genome editors and antisense cargos remains a central bottleneck. Addressing this challenge requires a quantitative understanding of transport across physiological barriers, productive cellular uptake, endosomal escape, and intracellular trafficking, together with manufacturability, stability, and quality attributes that enable translation.

This Special Issue aims to collate mechanism-anchored research that advances the efficacy, specificity, and safety of non-viral gene delivery vectors, positioned within the core disciplines of formulation science, biopharmaceutics, pharmacokinetics, and nanomedicine. We welcome submissions of multidisciplinary research that integrates materials design with data science, microfluidics, automation, or advanced imaging, encompassing lipid-, polymer-, peptide-, extracellular vesicle-, and inorganic-based carrier platforms.

For this Special Issue, original research articles and reviews are welcome to be submitted. Research areas may include, but are not limited to, the following:

  • Lipid, polymer, peptide, extracellular vesicle, and inorganic carrier platforms;
  • Tissue-selective targeting, biodistribution, and barrier traversal in vivo;
  • Cellular uptake pathways, endosomal escape mechanisms, and organelle routing;
  • Immune interactions, reactogenicity mitigation, and tolerability profiling;
  • Scalable manufacturing and CMC, including stability and analytical release testing;
  • Microfluidic synthesis, process intensification, and quality-by-design;
  • Quantitative PK/PD modeling, systems analysis, and imaging-guided tracking;
  • Delivery of CRISPR/Cas systems, base/prime editors, and antisense oligonucleotides;
  • mRNA and self-amplifying RNA vaccines, protein replacement, and gene modulation.

I look forward to receiving your contributions.

Dr. Hyun-Ouk Kim
Guest Editor

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Keywords

  • non-viral gene delivery
  • lipid nanoparticle
  • polymeric carrier
  • endosomal escape
  • genome editing delivery

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Published Papers (2 papers)

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Review

29 pages, 1256 KB  
Review
Industrial Perspective on the Manufacturing of Lipid Nanoparticles for Nucleic Acid Delivery
by Jenny Hong Hoang, Melanie Ott, Eleni Samaridou, Moritz Beck-Broichsitter and Johanna Simon
Pharmaceutics 2026, 18(4), 489; https://doi.org/10.3390/pharmaceutics18040489 - 16 Apr 2026
Viewed by 613
Abstract
Lipid nanoparticles (LNPs) have emerged as a groundbreaking delivery platform, revolutionizing the development of nucleic acid-based medicines for gene delivery and gene therapy. This review provides an insightful industrial perspective on the production process of LNPs, focusing on cutting-edge manufacturing equipment, downstream processing [...] Read more.
Lipid nanoparticles (LNPs) have emerged as a groundbreaking delivery platform, revolutionizing the development of nucleic acid-based medicines for gene delivery and gene therapy. This review provides an insightful industrial perspective on the production process of LNPs, focusing on cutting-edge manufacturing equipment, downstream processing and the crucial transition from laboratory to large scale. While LNP production in the discovery phase relies on a small scale (µL to mL) for screening various LNP formulation candidates, transferring to preclinical (up to hundreds of mL) and clinical/commercial scales (up to liters) requires a robust and reproducible manufacturing process. Thus, mixing technologies throughout these scales must be carefully selected and require precision, scalability and high reproducibility to meet the target quality of the LNP drug product. Key mixing technologies in mRNA-LNP production primarily include microfluidic systems and impinging jet mixers (IJMs). In this review, we discuss key critical process parameters (CPPs) in LNP preparation, including flow rate ratio (FRR) or total flow rate (TFR), in relation to associated critical quality attributes (CQAs) across multiple manufacturing scales. We further assess the impact of downstream processing, specifically tangential flow filtration (TFF), on the formulation’s CQAs. In particular, the review highlights the importance of maintaining CQAs along each step of the process and emphasizes the role of robust analytical methods in ensuring product quality and safety. Additionally, we touch on current challenges associated with these advanced delivery vehicles, such as their long-term stability, and introduce the readership to innovative stabilization strategies aimed to extent LNP shelf-life. Full article
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36 pages, 4341 KB  
Review
Physiological Barriers to Nucleic Acid Therapeutics and Engineering Strategies for Lipid Nanoparticle Design, Optimization, and Clinical Translation
by Yerim Kim, Jisu Park, Jaewon Choi, Minse Kim, Gyeongsu Seo, Jeongeun Kim, Jeong-Ann Park, Kwang Suk Lim, Suk-Jin Ha and Hyun-Ouk Kim
Pharmaceutics 2025, 17(10), 1309; https://doi.org/10.3390/pharmaceutics17101309 - 8 Oct 2025
Cited by 5 | Viewed by 3977
Abstract
Lipid nanoparticles are a clinically validated platform for delivering nucleic acids, but performance is constrained by multiscale physiological barriers spanning circulation, vascular interfaces, extracellular matrices, cellular uptake, and intracellular trafficking. This review links composition–structure–function relationships for ionizable lipids, helper phospholipids, cholesterol, and PEG-lipids [...] Read more.
Lipid nanoparticles are a clinically validated platform for delivering nucleic acids, but performance is constrained by multiscale physiological barriers spanning circulation, vascular interfaces, extracellular matrices, cellular uptake, and intracellular trafficking. This review links composition–structure–function relationships for ionizable lipids, helper phospholipids, cholesterol, and PEG-lipids to systemic fate, endothelial access, endosomal escape, cytoplasmic stability, and nuclear transport. We outline strategies for tissue and cell targeting, including hepatocyte ligands, immune and tumor selectivity, and selective organ targeting through compositional tuning, together with approaches that modulate escape using pH-responsive chemistries or fusion-active peptides and polymers. We further examine immunomodulatory co-formulation, route and schedule effects on biodistribution and immune programming, and manufacturing and stability levers from microfluidic mixing to lyophilization. Across these themes, we weigh trade-offs between stealth and engagement, potency and tolerability, and potency and manufacturability, noting that only a small fraction of endosomes supports productive release and that protein corona variability and repeat dosing can reshape tropism and clearance. Convergence of standardized assays for true cytosolic delivery, biomarker-guided patient selection, and robust process controls will be required to extend LNP therapeutics beyond the liver while sustaining safety, access, and scale. Full article
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