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

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.