Triple-negative breast cancer (TNBC) is a highly aggressive subtype with a poor prognosis. Current single-agent checkpoint therapy has limited effectiveness in TNBC patients. In this study, we developed doxorubicin-loaded platelet decoys (PD@Dox) for chemotherapy and induction of tumor immunogenic cell death (ICD). By combining PD-1 antibody, PD@Dox has the potential to enhance tumor therapy through chemoimmunotherapy in vivo. Methods: Platelet decoys were prepared using 0.1% Triton X-100 and co-incubated with doxorubicin to obtain PD@Dox. Characterization of PDs and PD@Dox was performed using electron microscopy and flow cytometry. We evaluated the properties of PD@Dox to retain platelets through sodium dodecyl sulfate-polyacrylamide gel electrophoresis, flow cytometry, and thromboelastometry. In vitro experiments assessed drug-loading capacity, release kinetics, and the enhanced antitumor activity of PD@Dox. The mechanism of PD@Dox was investigated through cell viability assays, apoptosis assays, Western blot analysis, and immunofluorescence staining. In vivo studies were performed using a TNBC tumor-bearing mouse model to assess the anticancer effects. Results: Electron microscopic observations confirmed that platelet decoys and PD@Dox exhibited a round shape similar to normal platelets. Platelet decoys demonstrated superior drug uptake and loading capacity compared to platelets. Importantly, PD@Dox retained the ability to recognize and bind tumor cells. The released doxorubicin induced ICD, resulting in the release of tumor antigens and damage-related molecular patterns that recruit dendritic cells and activate antitumor immunity. Notably, the combination of PD@Dox and immune checkpoint blockade therapy using PD-1 antibody achieved significant therapeutic efficacy by blocking tumor immune escape and promoting ICD-induced T cell activation. Conclusion: Our results suggest that PD@Dox, in combination with immune checkpoint blockade therapy, holds promise as a potential strategy for TNBC treatment.

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