Main-chain disulfide-linked cationic polycarbonates for local mRNA delivery

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Gene Delivery Systems

Background:

• Cationic polycarbonates are explored as biodegradable, low-toxicity gene vectors.
• Main-chain cationic polycarbonates with stimuli-responsive groups for mRNA delivery are underexplored.
• Existing vectors often focus on pendant cationic side chains, limiting design flexibility.

Purpose of the Study:

• To synthesize and characterize novel main-chain cationic polycarbonates for mRNA delivery.
• To evaluate the stimuli-responsive degradation and mRNA complexation capabilities of these polymers.
• To assess the transfection efficiency, biocompatibility, and in vivo performance of the developed mRNA delivery system.

Main Methods:

• Synthesis of main-chain cationic polycarbonates (Bn-pNC and Bn-p(NC-co-SSC)) via ring-opening polymerization.
• Characterization of polymer degradation profiles (pH- and reduction-responsive).
• Formation and characterization of polyplexes with mRNA, followed by in vitro (HEK 293T cells) and in vivo (intramuscular, intranasal administration) transfection studies.

Main Results:

• Bn-pNC showed pH-responsive degradation; Bn-p(NC-co-SSC) exhibited dual pH- and reduction-responsive degradation.
• Both polymers formed nanosized, positively charged polyplexes with mRNA.
• Bn-p(NC-co-SSC) polyplexes demonstrated superior transfection efficiency and biocompatibility in vitro and in vivo compared to commercial poly(ethylenimine).
• In vivo studies showed effective transfection at administration sites and sustained protein expression, acting as localized drug depots.

Conclusions:

• Main-chain cationic polycarbonate Bn-p(NC-co-SSC) is a safe and effective mRNA delivery system.
• Dual pH- and reduction-responsive degradability enhances therapeutic potential.
• This polymer platform holds promise for vaccine development and long-acting protein therapies.