Shellac‐Mediated Assembly of Nanoparticles for mRNA Delivery

Cationic polymers have been extensively explored for messenger RNA (mRNA) delivery owing to their ability to condense nucleic acids and facilitate cellular uptake. High-molecular-weight polymers typically achieve high transfection efficiency but exhibit substantial cytotoxicity, whereas low-molecular-weight polymers show reduced cytotoxicity but low transfection efficiency. To address the tradeoff between toxicity and transfection efficiency, herein, we present a simple and versatile shellac (SL)-mediated assembly strategy, whereby mRNA is complexed with low-molecular-weight cationic polymers (e.g., polyethyleneimine) and subsequently stabilized by SL to form nanoparticles under mild conditions. The SL-based nanoparticles exhibit >90% mRNA encapsulation efficiency and enable mRNA transfection across various cell types while showing negligible cytotoxicity. Furthermore, the SL-based nanoparticle platform enables protein expression and gene editing in mice through both intravenous and oral administration routes. This work highlights the potential of SL as a key building block to direct the assembly and delivery of mRNA, enabling the rational design of modular and versatile nucleic acid delivery platforms for diverse biological applications.