In Situ Construction of a Reticulated Peptide Scaffold via Responsive Self-Assembly and Proximal Covalent Labeling for Enhanced Tumor Imaging and Therapy

Abstract Precise imaging and specific retention of therapeutic agents at solid tumors were particularly desirable yet hindered by limited specificity and fast diffusion. Herein, we established a dual-trigger-mediated synergistic strategy to form a reticulated peptide network in situ by functional peptide (CL-YPFG) through responsive self-assembly and covalent labeling for prolonged imaging and boosted accumulation of drugs. Specifically, the CL-YPFG underwent morphology transformation from nanoparticles to nanofibers under alkaline phosphatase and further turned into reticulated peptide structures in the presence of nitroreductase by generating highly electrophilic quinone methide intermediates for covalent labeling of proximal peptides or proteins, enabling prolonged tumor retention. By replacing the functional groups on CL-YPFG, it could be readily endowed with imaging (organic dyes for fluorescence imaging and chelator moieties for 1H magnetic resonance imaging) and therapeutic (photodynamic therapy and immunotherapy) capabilities, demonstrating the versatility of peptide-based scaffolds for enhanced tumor-specific imaging/therapy.