Resolving the mRNA Encapsulation‐Release Trade‐off via Compensatory Forces in Engineered Ionizable Lipids

Abstract A critical challenge in lipid nanoparticle (LNP) delivery of messenger RNA (mRNA) is the inherent trade‐off between stable encapsulation and efficient intracellular release. Here, this challenge is addressed through rationally engineering compensatory forces between mRNA and LNP, leveraging short‐range intermolecular interactions (van der Waals, hydrogen bonding) to dynamically balance long‐range Coulombic binding. Guided by a computational‐experimental framework, a “contact number” metric is developed to decipher mRNA and LNP binding hierarchies, enabling the strategic incorporation of short‐range‐interaction motifs (e.g., urea, carbamate) into ionizable lipid (IL) structures. These designs achieve optimal mRNA encapsulation while promoting endosomal escape and cytosolic release, resulting in enhanced mRNA translation. Compared to commercial mRNA vaccine counterparts, the engineered LNP (OT13‐LNP) induces a 1.7‐fold increase in antigen‐specific T cell responses and 77.9% tumor inhibition in melanoma. In hepatic gene editing, OT13‐LNPs achieve comparable transthyretin (TTR) on‐target editing efficiency to ALC0315‐LNPs (0.5 mg kg −1 ), but elicit a markedly stronger silencing effect, reducing serum TTR levels by over 90% compared with ≈58% for ALC0315‐LNPs. This study may highlights the potential of compensatory‐force engineering for next‐generation mRNA therapeutics in oncology, gene editing, and infectious diseases.