Topology-Programmed Peptide Architectures Orchestrate Durable Tumor Targeting and Cascade Antitumor Immunity

Abstract Peptide supramolecular systems offer recognition and biocompatibility for precision theranostics, yet their in vivo performance is limited by insufficient structural stability, poor retention, and loss of accessible recognition interfaces under physiological perturbations. Herein, a topology-programmed supramolecular assembly strategy was developed to stabilize adaptive peptide architectures through confinement-guided organization. A β-sheet-based peptide EH, with PD-L1 (programmed death-ligand 1) targeting, favorable assembly behavior, and hydrophobic anchoring potential, was screened from an amphiphilic peptide library and integrated with immunoactivating SeAD quantum dots into PLGA (poly(lactic-co-glycolic acid)) microspheres featuring an interconnected hydrophobic channel network. This network guides channel-confined EH assembly through hydrophobic anchoring and β-sheet reinforcement, enabling ordered nanofiber alignment while preserving local conformational flexibility and exposed recognition motifs. This topology-programmed assembly converts dynamic peptide fibers into a structurally stabilized supramolecular interface, leading to prolonged tumor retention and sustained local immune checkpoint blockade. Meanwhile, ultrasound-activated SeAD induces immunogenic cell death and systemic antitumor immunity. By coupling confinement-stabilized peptide recognition with sonodynamic immune activation, EHSeAD@MS achieves durable local tumor intervention, immune microenvironment remodeling, and suppression of distant and metastatic lesions. It establishes a molecular design principle for balancing structural integrity and adaptive recognition in peptide supramolecules, providing a strategy for long-lasting peptide-based cancer immunotherapy.