Abstract

Chemotherapy for peritoneal metastases (PM) is severely constrained by the limited intratumor drug penetration and insufficient retention within tumors. Herein, we rationally engineer a fibroblast activation protein (FAP)-triggered transformable nanoassembly of peptide-drug conjugate to address these bottlenecks for PM chemotherapy. We identify 7-ethyl-10-hydroxy-camptothecin (SN38) as the preferred cytotoxic agent and C-X-C motif chemokine ligand 16 (CXCL16)-mimic peptide as the selected tumor-penetrating peptide, which are conjugated via a FAP/glutathione-dual responsive linker to form a SN38-STPC 16 conjugate. SN38-STPC 16 is further assembled with pre-screened 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol) 1000] (DMPE-PEG 1000 ) to construct transformable nanoassemblies (SN38-STPC 16 NA). SN38-STPC 16 NA undergoes FAP-triggered transformation into nanofibers and GSH-responsive drug release. Both in murine CT26 PM model and patient-derived xenograft (PDX)-PM model, SN38-STPC 16 NA achieves efficient intratumor penetration and prolonged retention in PM lesions, causing notable inhibition of PM progression. Especially in PDX-PM model, SN38-STPC 16 NA reduces PM tumor weight by 80.9%, decreases PM nodule number by 82.3%, and extends median survival by 1.76-fold, outperforming the clinical standard FOLFIRI regimen. Collectively, the transformable SN38-STPC 16 NA represents an encouraging delivery platform for effective PM chemotherapy.