Biodegradable Polymers for Gene-Delivery Applications

Purpose: Gene therapy is limited by the fragile nature of therapeutic DNA/RNA and by safety concerns with viral vectors. Non-viral polymeric vectors are attractive, but conventional cationic polymers such as PEI, PDMAEMA, and PLL are often non-degradable, causing accumulation, cytotoxicity, and poor gene unpacking. This review addresses the need for biodegradable polymeric vectors that maintain transfection efficiency while improving biocompatibility and biosafety, especially for repeated administration.

Hypothesis: This is a review article and does not test a single formal hypothesis. Its central premise is that biodegradable polymers — natural, synthetic, and bioreducible — can overcome the cytotoxicity and accumulation problems of non-degradable cationic polymers while preserving gene delivery capacity, because their hydrolytically or reductively cleavable linkages enable polymer degradation, body clearance, and triggered intracellular gene release.

Aims: Define and categorize biodegradable polymers and describe their degradation mechanisms. - Introduce natural biodegradable polymers for gene delivery, including protein- and polysaccharide-based vectors. - Review synthetic biodegradable polymers, including polyesters, polycarbonates, and polyurethanes. - Describe bioreducible polymers designed with cleavable linkages such as disulfide bonds. - Provide future perspectives for next-generation biodegradable polymer gene-delivery vectors.

Delivery system: Vector type: Cationic polymer/gene polyplexes formed by electrostatic interaction; typical size a few hundred nanometers; taken up by endocytosis; endosomal escape via proton-sponge or swelling/mechanical disruption; gene unpacking via polymer degradation. - Natural biodegradable polymers: Protein-based — gelatin, albumin, collagen. Polysaccharide-based — chitosan (CS), hyaluronic acid (HA), dextran, β-cyclodextrin (β-CD). - Synthetic biodegradable polymers: Polyesters — PHP, PAGA, PBAE, PVL, aminated PAHA, PPE, PLA, cationic polylactides (CPLAs). Polycarbonates (PCs). Polyurethanes (PUs). - Bioreducible polymers: Disulfide-containing PEI derivatives, poly(amido ethylenimine) (PAA), poly(cystaminebisacrylamide-diaminohexane) [poly(CBA-DAH)]. - Payloads: Plasmid DNA (pDNA), siRNA, miRNA, oligonucleotides; also drug/gene co-delivery. - Targeting/functional ligands: Folate, hyaluronic acid (CD44), RGD peptide, galactose, Tat, and others.

Approach: Review of in vitro and in vivo literature. Model systems include numerous cancer cell lines (e.g., HeLa, A549, MCF-7, 293T, COS-7, U87, HNE-1, pancreatic and leukemic cancer cells) and animal models (tumor-bearing mice, lung metastasis, glioblastoma, etc.). No new primary experiments are reported.

Key methods: Polyplex characterization: Size, surface charge, gel electrophoresis, DLS/zeta potential, TEM/AFM. - Transfection/gene silencing: Luciferase and GFP reporter expression; siRNA-mediated knockdown. - Cytotoxicity/biocompatibility: MTT assays, hemolysis, cell viability. - Cellular uptake and intracellular trafficking: Fluorescent labeling, confocal microscopy. - In vivo efficacy: Tumor growth inhibition, metastasis reduction, survival time, biodistribution. - Degradation: Hydrolytic and reductive cleavage of polymer backbones/linkages.

Key results: PHP: Degraded to half its original molecular weight in <2 h; complete degradation in about 3 months; transfection efficiency comparable to PLL and not significantly affected by serum proteins. - PAGA: Polyplexes showed 3-fold higher transfection efficiency than PLL with significantly reduced cytotoxicity. - PVL: Optimal functional PVL copolymer showed 2.2-fold higher transfection efficiency than PEI. - Bioreducible PEI: Disulfide cross-linked PEI (PEI-SS) polyplexes had higher transfection efficiency and lower cytotoxicity than non-degradable counterparts. - RGD-PEG-SS-PEI: Improved transfection and reduced cytotoxicity in U87 cells and enhanced gene expression in the brain of intracranial U87 glioblastoma-bearing mice. - Cationic bovine serum albumin (CBSA)/siRNA: Efficient gene silencing, induced cancer cell apoptosis, and inhibited tumor growth in a B16 lung metastasis model.

Interpretation: Biodegradability is a critical material feature for clinical translation of gene-delivery vectors, especially because gene therapy often requires repeated administration. Biodegradable polymers can reduce accumulation and toxicity, improve biosafety, and facilitate intracellular gene unpacking and release. Despite favorable properties, translation from in vitro to in vivo and clinical trials still faces major biological barriers. The authors recommend future work on clear structure–function relationships, enhanced in vivo stability, targeting/imaging functions, more rigorous in vivo assessment, and spatially/temporally controlled gene release.

Limitations: This is a review, not a primary study; no new experimental data or meta-analysis. - Most discussed systems remain preclinical; clinical translation remains an immense challenge. - A large gap persists between in vitro results and in vivo performance. - Structure–function relationships for biodegradable polymer vectors are not yet fully elucidated. - Long-term fate of degradation products, chronic toxicity, and large-animal validation are not deeply addressed. - Controlled release profiles and timely gene unpacking require further investigation.