Transformable nanoassembly of CXCL16 peptide-SN38 conjugate improves intratumor permeation and retention in peritoneal metastases.

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-STPC16 conjugate. SN38-STPC16 is further assembled with pre-screened 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol) 1000] (DMPE-PEG1000) to construct transformable nanoassemblies (SN38-STPC16 NA). SN38-STPC16 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-STPC16 NA achieves efficient intratumor penetration and prolonged retention in PM lesions, causing notable inhibition of PM progression. Especially in PDX-PM model, SN38-STPC16 NA reduces PM tumor weight by 80.9%, decreases PM nodule number by 82.3%, and extends median survival by 1.81-fold, outperforming the clinical standard FOLFIRI regimen. Collectively, the transformable SN38-STPC16 NA represents an encouraging delivery platform for effective PM chemotherapy.