Receptor‐Triggered Peptide Self‐Assembly Enables Multivalent Recruitment of Endogenous Antibodies for Cancer Immunotherapy

ABSTRACT

Monoclonal antibody–based immunotherapies have achieved remarkable clinical success but remain limited by variable patient responses, immune‐related toxicities, and the complexity of antibody production. Antibody‐recruiting molecules (ARMs) offer an alternative strategy by harnessing endogenous antibodies to induce immune‐mediated tumor clearance; however, their therapeutic efficacy is often constrained by insufficient antibody recruitment arising from weak hapten–antibody interactions. Here we report a receptor‐triggered supramolecular assembly strategy that converts monovalent antibody recruiters into multivalent immunotherapeutic platforms directly on cancer cell surfaces. An EGFR‐targeting peptide (GE11) was conjugated with a dinitrophenyl (DNP) hapten and a short self‐assembly motif to afford a monomeric construct that undergoes EGFR‐mediated in situ self‐assembly into fibrillar networks on EGFR‐overexpressing cells. This receptor‐guided supramolecular transformation generates a high‐density multivalent display of haptens on the cell membrane, enabling efficient recruitment of endogenous anti‐DNP antibodies. The resulting assemblies induce potent complement‐dependent cytotoxicity (CDC) against EGFR‐positive cancer cells in vitro and produce significant antitumor efficacy in tumor‐bearing mouse models with minimal systemic toxicity. This work establishes receptor‐mediated peptide self‐assembly as a general supramolecular strategy for transforming monovalent antibody recruiters into multivalent immunotherapeutic platforms, providing a new framework for the design of selective ARMs for cancer immunotherapy.