Polymeric Delivery System for mRNA Therapeutics: Design Principles and Recent Advances.

Messenger RNA (mRNA) therapeutics are redefining treatment approaches in vaccines, cancer immunotherapy, protein replacement, and gene editing. Lipid nanoparticles have enabled early clinical successes, but they can be limited by liver-dominant biodistribution, long-term storage stability, and systemic tolerability. Polymeric delivery systems offer a versatile alternative, with tunable physicochemical properties enabling precise control over mRNA complexation, protection, release, and targeting. This review examines recent progress across polyethyleneimine derivatives, poly(β-amino ester)s, poly(amino acid)s, polyesters, dendrimers, charge-altering releasable transporters, and lipid-polymer hybrids. We highlight strategies such as structural modification, stimuli-responsive designs, and high-throughput polymer screening that enhance stability, reduce cytotoxicity, and enable organ- or cell-specific delivery. Addressing challenges in immunogenicity, biodistribution, and manufacturing scalability will be pivotal to translating these innovations into safe and effective mRNA therapeutics.