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.
张 et al. (Tue,) studied this question.