Bioengineering of BRAF and COX2 inhibitor nanogels to boost the immunotherapy of melanoma via pyroptosis.

Glutathione-responsive nanogels (CDNPs) crosslinked via crosslinker DBHD with the BRAF inhibitor dabrafenib and the COX2 inhibitor celecoxib were fabricated. The CDNPs can effectively induce tumor cell pyroptosis to activate robust antitumor immunity. Additionally, CDNPs combined with αPD-1 antibody greatly inhibited tumor growth in a melanoma mouse model with a prolonged survival time.

Stepwise Size Shrinkage Cascade-Activated Supramolecular Prodrug Boosts Antitumor Immunity by Eliciting Pyroptosis.

Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH-activated supramolecular nanoprodrug (PDNP) with a stepwise size shrinkage property is developed as a pyroptosis inducer to boost antitumor immune response. PDNPs comprise multiple poly(ethylene glycol) (PEG) and doxorubicin (DOX) drug-polymer hybrid repeating blocks conjugated by ultra-pH-sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its "stealth" property and ensure sufficient tumor accumulation. A sharp switch in particle size and detachment of PEG shielding can be triggered by the acidic extracellular pH to achieve deep intratumor penetration. Following endocytosis, second-stage size switching can be initiated by more acidic endolysosomes, and PDNPs disassociate into ultrasmall cargo to ensure accurate intracellular delivery. The cascaded pH activation of PDNPs can effectively elicit gasdermin E (GSDME)-mediated pyroptosis to enhance the immunological response. In combination with anti-PD-1 antibody, PDNPs can amplify tumor suppression and extend the survival of mice, which suggests a powerful immune adjuvant and pave the way for high-efficiency immune checkpoint blockade therapy.