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.

Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the issues of rapid tumor clearance and insufficient cellular translocation. In this work, we demonstrate that a transactivator of transcription (TAT)-presenting nanomedicine (^DATAT-NP/Pt), apart from improving tumor accumulation and cellular uptake, can simultaneously enhance tumor retention and promote nuclear translocation of encapsulated platinum prodrugs, and thus improve therapeutic efficacy. Specifically, a protecting 2, 3-dimethylmaleic anhydride (DA) corona on the nanomedicine prevented the TAT peptide from serum. ^DATAT-NP/Pt efficiently accumulated at the tumor site through the enhanced permeability and retention (EPR) effect, followed by acid-triggered TAT presenting within the tumor acidic microenvironment (pH ~ 6.8). The exposed TAT peptide augmented tumor retention and nuclear translocation of ^DATAT-NP/Pt. We used a tumor-on-a-chip microfluidic system to real-time mimic and analyze tumor accumulation and retention at physiological flow conditions and revealed that surface absorption of nanomedicines on tumors was critical in determining their tumor retention and clearance. Furthermore, the TAT peptide rapidly translocated the ^DATAT-NP/Pt into the perinuclear region, allowing for higher nuclear platinum concentrations and increased Pt-DNA adduct formation in nuclei, which consequently reversed cisplatin resistance. Our work presents a new strategy to overcome pathophysiological barriers of tumor clearance and insufficient cellular translocation and provides new insights for the design of cancer nanomedicines.