Silk-Based Protein Corona Enhances mRNA-LNP Vaccine Efficacy and Prevents Tumor Relapse.

Lipid nanoparticles (LNPs) are clinically validated carriers for nucleic acid therapeutics; however, achieving targeted delivery to reticuloendothelial organs beyond the liver, lung, and spleen remains a major challenge. Here, we introduce a strategy for post-fabrication engineering of a custom protein corona on mRNA-LNPs using cationic silk fibroin (SF), a biocompatible and chemically tunable protein polymer. SF-coated LNPs exhibit enhanced cellular uptake and endosomal escape, resulting in a 3.6 fold increase in lymph node delivery and a 2.5 fold extension in in vivo protein expression compared to unmodified LNPs. In a cancer vaccine model, SF-LNPs significantly improve dendritic cell maturation, antigen cross-presentation, and cytotoxic T cell activation, leading to robust protection against tumor growth and metastasis, as well as durable immunological memory. This work expands the formulation space for LNPs and establishes silk fibroin as a modular surface engineering tool for enhancing the efficacy and specificity of mRNA-based therapeutics.