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.
Mingzhe Zhang, Chunhong Wang, Xiaohan Xu et al.· Journal of the American Chem...· 0 citations
Drug conjugates, such as antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs), are often dependent on efficient receptor-mediated endocytosis for payload release1-3-supported by about 10% of targets4-7. For poorly internalizing targets, drug conjugates dissociate and clear rapidly, limiting efficacy. To overcome the limitation in the internalization-to-release (ITR) pattern, we introduce a binding-to-release (BTR) strategy that decouples drug release from endocytosis by positioning an electrophile for direct cleavage by a proximal nucleophilic residue within the binding pocket. To realize this, we developed phosphorus(V)-phenol exchange (PhoPEx), a sulfur(VI) fluoride exchange-inspired chemistry enabling release of various payloads. This platform demonstrated high specificity from in vitro to clinical specimens, achieving precise detection of fibroblast activation protein (FAP) expression in patient-derived lymph nodes. In therapeutic settings, the FAP-BTR-SMDC achieved 5.9-fold higher monomethyl auristatin E exposure (AUC0-120 h) in tumours than internalization-dependent FAP-ITR-SMDC, matching FAP-ITR-ADC levels while minimizing off-target release. This led to improved ratios: the tumour-to-blood ratio was 14.7- and 3.6-fold higher than that of FAP-ITR-SMDC and FAP-ITR-ADC, respectively, and the tumour-to-liver ratio was 55.1- and 58.7-fold higher, respectively. This biodistribution increased the maximum tolerated dose and led to near-complete tumour regression in various tumour models. We further extended BTR to programmed cell death ligand 1 (PD-L1) and an mRNA-display-derived FAP peptide, suggesting potential broad applicability. This work establishes a framework that overcomes the internalization barrier, broadening the target scope for therapeutic and diagnostic conjugates.
Zihao Wen, Mengxin Xu, Zi-Jun Yan et al.· Nature· 0 citations