High drug loading and pH-responsive nanomedicines driven by dynamic boronate covalent chemistry for potent cancer immunotherapy

Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce ICD, however accompanied with severe adverse effects in the clinic, weakening its immune responses. Herein, to elicit an intensive ICD while minimizing the systemic toxicity, we introduce a tumor targeting peptide modified bortezomib (BTZ) loading nanomedicine (i-NP_BTZ) for the efficient delivery and controlled release of BTZ in tumors. This system is constructed by conjugating BTZ to PEGylated polyphenols via a pH-sensitive covalent boronate–phenol bond that allows them to self-assemble into nanovesicles in neutral condition with high drug loading efficiency. Once accumulated in acidic environment, BTZ–phenolic network is disassembled and thereby accelerates the release of BTZ from nanocarriers. The released BTZ selectively kill tumor cells with a concomitant evocation of tumor-specific cytotoxic T cells by triggering ICD in vivo. This can finally lead to an extended tumor ablation and prevention of distant metastasis in a syngeneic tumor mouse model, while reducing the systemic toxicity of BTZ. In general, our system offers a novel concept with clinical potential to exploit ICD for potentiating tumor immunotherapy and also provides an excellent example of the application of polymer–drug interaction for efficient drug delivery and controllable release.