Biodegradable Polymer Nanogels for DrugNucleic Acid Delivery

Purpose: Despite extensive research, therapeutic delivery still faces major barriers: poor plasma stability, rapid clearance by the reticuloendothelial system (RES), and intracellular obstacles such as endosomal entrapment and lysosomal degradation. Biodegradable polymer nanogels (NGs) — physically or chemically cross-linked, water-swollen, submicrometer hydrophilic polymer networks — are promising because they can encapsulate or conjugate drugs/nucleic acids, respond to stimuli, and degrade into eliminable fragments. This review systematically covers biodegradable NGs based on natural and synthetic polymers for drug and nucleic acid delivery.

Hypothesis: This is a review article and does not test a single formal hypothesis. Its central premise is that biodegradable NGs can overcome delivery barriers through rational design — combining biocompatibility, controllable degradation, stimuli-responsive release, targeting ligands, and favorable pharmacokinetics/biodistribution — to improve therapeutic efficacy and reduce toxicity for drugs and nucleic acids.

Aims: Summarize general preparation approaches for biodegradable NGs: electrostatic interaction, reverse miniemulsion, desolvation/coacervation, hydrophobic interaction, and cross-linking of micelles. - Review natural polymer-based NGs, including chitosan, pullulan, dextran, hyaluronic acid, alginate, heparin, gelatin, and others. - Review synthetic polymer-based NGs, including polypeptides, PEG, polyglycerol, and polyacrylamide, including partially degradable systems with degradable cross-links. - Discuss drug release behavior, biodegradability, biocompatibility, therapeutic efficacy, cell uptake mechanisms, pharmacokinetics, and biodistribution. - Highlight current challenges and future perspectives for clinical translation.

Delivery system: Nanogel type: Physically or chemically cross-linked 3D hydrophilic polymer networks, typically up to a few hundred nanometers, swelling in water. - Natural polymers: Chitosan (CTS), pullulan (PUL), dextran (DEX), hyaluronic acid (HA), alginate (ALG), heparin (HEP), gelatin (GEL), chondroitin sulfate, cycloamylose, glucan, curdlan, hydroxypropyl cellulose, dextrin. - Synthetic polymers: Polypeptides (PPT), poly(ethylene glycol) (PEG), polyglycerol dendrimers (PG), polyacrylamide (PAm), and partially degradable systems with stimuli-sensitive cross-linkers. - Payloads: Anticancer drugs (DOX, PTX, cisplatin, temozolomide, tamoxifen, retinoic acid), proteins/peptides (insulin, IL-12, BMP-2, exendin-4, RNase A, caspase 3, antigens), and nucleic acids (pDNA, siRNA, antisense oligonucleotides, mRNA/microRNA in related contexts). - Targeting ligands: Folic acid, RGD peptide, galactose, hyaluronic acid/CD44, glycyrrhizin, biotinylated EGF, and others. - Stimuli responsiveness: pH, redox/GSH, temperature, enzymes, light/photothermal, magnetic, ultrasound. - Preparation methods: Electrostatic interaction, reverse miniemulsion, desolvation/coacervation, hydrophobic interaction, cross-linking of micelles.

Approach: Review of in vitro and in vivo literature. Model systems include cancer cell lines (HeLa, MCF-7, A549, HepG2, SCC7, HCT-116, KB, 293T, COS7, CHO, etc.) and animal models (mice, rats, rabbits) for cancer, diabetes, bone regeneration, wound healing, tuberculosis, inflammation, and gene silencing. No new primary experiments are reported.

Key methods: Preparation/characterization: DLS, TEM/SEM, zeta potential, FTIR, NMR, and related methods. - Loading/release: Encapsulation efficiency, drug loading, release profiles under pH, redox, temperature, enzyme, or light triggers. - Cellular uptake: Confocal microscopy, flow cytometry, endocytosis pathway inhibitors. - In vivo: Pharmacokinetics, biodistribution (NIRF imaging), therapeutic efficacy (tumor growth inhibition, bone formation, hypoglycemia, etc.), biocompatibility/toxicity.

Key results: Chitosan/alginate NGs improved gene transfection in 293T cells 4-fold compared with CTS NGs without alginate. - Redox-sensitive HA NGs protected siRNA; 94% remained entrapped after 110 min without GSH, while at 10 mM GSH siRNA was completely released within 60 min. - Pullulan CHP NGs showed chaperone-like refolding of acid-denatured GFP: about 90% fluorescence recovered within 10 min after β-cyclodextrin addition, almost equal to the natural GroEL–GroES system. - Ca-ALG/CTS NGs maintained antitubercular drugs above MIC90 for 15 days in mice, versus 1 day for free drugs; dosing frequency was reduced 15-fold. - PEGylated HA NGs showed lower liver uptake, increased circulation time, and up to 1.6-fold higher tumor accumulation than bare HA-CA NGs. - Polyacrylamide CP3 NGs induced apoptosis in HeLa and MCF-7 cells with IC50 ~300 nM, and in U-87 MG cells with IC50 ~600 nM, whereas nondegradable NGs caused no significant cell death. - Size effect: smallest CTS/TPP NGs (182 nm) showed burst release, while medium (281 nm) and large (602 nm) NGs gave sustained release over 5 days. - HA NGs showed no apparent cytotoxicity to HCT-116 cells up to 1 mg/mL, whereas nondegradable PEI was cytotoxic at 0.1 mg/mL.

Interpretation: Biodegradable NGs from natural and synthetic polymers are promising intelligent carriers for drugs and nucleic acids because of their biocompatibility, high aqueous dispersibility, well-defined structure, easy loading, stimuli-responsive release, targeting capability, and flexibility/softness that can prolong circulation and improve tissue penetration. They can deliver therapeutics in a spatial-temporal manner, improve pharmacokinetics/biodistribution, and enhance efficacy while reducing side effects. The authors suggest that integrating multiple functions — dual targeting, codelivery, and controlled placement in artificial ECM — is a key future direction for clinical translation.

Limitations: This is a review, not a primary study; no new experimental data or meta-analysis. - Most systems remain preclinical; clinical data are limited. - Studies are heterogeneous in methods, models, and endpoints, limiting direct comparison. - Long-term safety, fate of degradation products, immunogenicity, scalable manufacturing, and regulatory issues are not fully resolved. - Some synthetic polymers are nondegradable or only partially degradable, and in vivo degradation/elimination mechanisms remain poorly understood. - No large-animal validation or clinical trial data are presented.