The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor-specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual-responsive nano-prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual-responsive system facilitates the nano-prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo-photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo-photodynamic therapy and control-release PTX synergistically induce gasdermin E (GSDME)-related pyroptosis. It is speculated that inspired chemo-photodynamic therapy using the presented nano-prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.

No abstract

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.

Chemotherapy is currently the most universal therapeutics to tumor treatment; however, limited curative effect and undesirable drug resistance effect are the two major clinical bottlenecks. Herein, we develop a two-in-one cross-linking strategy to prepare a stimuli-responsive prodrug nanogel by virtue of delivering a combination of chemotherapeutic drugs of 10-hydroxy camptothecin and doxorubicin for ameliorating the deficiencies of chemotherapy and amplifying the cancer therapeutic efficiency. The obtained prodrug nanogel has both high drug loading capacity and suitable nanoscale size, which are beneficial to the cell uptake and tumor penetration. Moreover, the chemotherapeutic drugs are released from the prodrug nanogel in response to the reductive tumor microenvironment, enhancing tumor growth inhibition in vitro and in vivo by the synergistic DNA damage. Based on these results, the unique prodrug nanogel would be a promising candidate for satisfactory tumor treatment-based chemotherapy by a simple but efficient strategy.

No abstract