A Bioorthogonal DesilylationSystem Potentiates mRNATherapeutics in Tumors

Abstract Lipid nanoparticle (LNP)-mediated mRNA delivery has emerged as a powerful therapeutic modality, yet its clinical translation in oncology remains constrained by inherent hepatic tropism and inefficient endosomal escape. These limitations necessitate high-dose administration, which triggers lipid-associated toxicity and off-target protein expression in the liver. To overcome these barriers, we report a cleavable silyl-ether-based bioorthogonally activatable LNP platform, termed SiLNP, that enables tumor-specific activation and cytosolic mRNA release. We engineered ionizable lipids incorporating silyl ether structural fuses that respond to a phenylalanine trifluoroborate (Phe-BF3) trigger. This system leverages the upregulated transporter LAT-1 to actively import Phe-BF3 into tumor cells, where it triggers lipid desilylation and rapid cargo release. In vitro, SiLNPs demonstrated controllable external control over mRNA expression, achieving a 44-fold enhancement in mRNA expression compared to standard SM-102 LNPs with a 10-fold activation-to-silent ratio. In immunologically “cold” B16–F10 melanoma models, SiLNPs encoding the N-terminal domain of gasdermin D (GDNT) induced tumor-specific pyroptosis, resulting in tumor growth inhibition without detectable systemic toxicity. Furthermore, this platform demonstrated versatility by delivering immunomodulatory mRNAs, including IL-2 and Cxcl9. Taken together, this work presents a metabolically targeted, bioorthogonal-activated delivery strategy to address the selectivity and efficiency limitations of current mRNA medicines, providing a promising platform for precision oncology.