Iterative Upgrading of mRNA Therapeutics by Modulating the Microenvironment for Translation

Abstract mRNA‐based non‐immunotherapy applications, instead of vaccines, require a high translational yield without immune activation. However, the intrinsic immunogenicity of mRNA therapeutics activates innate immunity, leading to decreased mRNA stability, mediocre protein production, and increased safety risks. Substantial efforts have been invested in addressing this challenge, which primarily focuses on the engineered structural and biochemical modifications of mRNA molecules and their packaging system. Nevertheless, current endeavors to satisfy the peculiarities of therapeutic mRNA are almost at the preclinical stages of development. Here, a third strategy termed environment‐adaptable collaborative regulating (EACR), is reported for de‐immunized delivery of mRNA therapeutics. A series of EACR candidates capable of modulating the microenvironment for therapeutic mRNA translation are identified through high‐throughput screening over an FDA‐approved drug library. Specifically, a Celecoxib (CXB)‐based EACR lipid nanoparticle is optimized for mRNA‐mediated regenerative angiogenesis, which displays augmented therapeutic protein expression and satisfactory biosafety in a mouse model of acute myocardial infarction (MI). EACR is compatible with all existing improvement strategies and is envisioned to unlock the promise of mRNA for non‐immunotherapy applications including regenerative medicine, protein replacement/supplementation therapy, and targeted genome engineering.