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

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.