Perivascular delivery of photothermal-immunotherapy nanovaccine bypasses blood circulation to enhance the antitumor immune response of breast cancer

Nanovaccines, with the synergistic effect of photothermal-immunotherapy, are one of the most advanced approaches for improving antitumor outcomes. However, targeted nanovaccine delivery to the tumor and draining lymph nodes remain critical obstacles due to the complex tumor microenvironment. Herein, we discovered a new drug delivery route of intervaginal space injection (ISI) to target tumor tissue and draining lymph nodes to bypass blood circulation. The synthesized nanoplatform (PDA/ICG/CpG, PIC) was integrated with polydopamine (as a photosensitizer), indocyanine green (as the imaging probe), and CpG ODN (as the immune adjuvant) for fluorescence imaging-guided photothermal-immunotherapy. After being injected via ISI, the nanovaccine accumulated excellently in the tumor and drained the lymph node, owing to the integrity of the interstitial structure and fluid flow. The tumor microenvironment, which has severely hindered drug delivery in recent research, may facilitate transportation via ISI. Under laser irradiation, tumor cells were killed by hyperthermia, whereby tumor-related antigens were released to promote the maturation of dendritic cells (DCs), evoking T lymphocyte activation. Aided by CpG, DC maturation, and CD8 + T-cell infiltration into the tumor, draining lymph nodes and spleen were significantly amplified. PDA/ICG/CpG injected via the interstitial space of the carpal tunnel effectively inhibited tumor growth and metastasis in a 4T1-bearing mammary model. This study provided different insights into targeted drug delivery. Nanovaccines with photothermal-immunotherapy of a suitable size that is administered via ISI have the potential to enable precise cancer treatment. • Novel PDA/ICG/CpG nanoplatform injected via ISI targets tumors and draining lymph nodes effectively bypass EPR effect. • Combined photothermal-immunotherapy via ISI significantly inhibits tumor growth. • CpG-aided DC maturation amplifies CD8 + T-cell response in tumors and lymph nodes. • ISI administration shows promise for precise and effective cancer treatment.