Potentiating Antibody‐Dependent Cell‐Mediated Cytotoxicity via Tumor‐Specific Anchoring and Activation of Nano‐Haptens

Abstract

ABSTRACT Tumor‐surface antigen deficiency and immunosuppressive tumor microenvironment (TME) hurdle the efficacy of antibody‐dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells. Here, acid‐activatable, polypeptide‐based nano‐haptens are developed and coupled with glycometabolism‐mediated tumor labeling to potentiate NK cell‐mediated ADCC. The nano‐haptens comprise chemotactic peptide (WKYMVm)‐encapsulated hollow mesoporous silica nanoparticles (HMSNs) that are shelled by conformation‐transformable polypeptides containing conjugated dibenzocyclooctyne (DBCO) and dinitrophenyl derivative (FDNB) at the backbone termini. In tumor‐bearing mice, an unnatural sugar (DCL‐AAM) was used to glycometabolically label tumor cell surfaces with azido groups, followed by systemic administration of the nano‐haptens. During blood circulation, the negatively charged, random‐coiled polypeptides flatly stack on the HMSN surface, preventing WKYMVm leakage and shielding the FDNB and DBCO domains. Inside the acidic TME, the polypeptides transform into positively charged, rigid α‐helices, unmasking the pores and releasing WKYMVm to enhance intratumoral infiltration of NK cells. Concurrently, DBCO and FDNB are conditionally exposed to enable anchoring of nano‐haptens onto azido‐labeled tumor cells and binding of endogenous anti‐dinitrophenyl, respectively, thereby bridging tumor cells and NK cells to assist robust ADCC. When further coupled with anti‐Ly49C that ameliorates the immunosuppressive TME, the nano‐haptens achieve potent tumor elimination and induce durable adaptive immunity to prevent tumor recurrence.