A binding-to-release strategy for targeted anticancer drug delivery.
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.