Native Mitochondria-Targeting polymeric nanoparticles for mild photothermal therapy rationally potentiated with immune checkpoints blockade to inhibit tumor recurrence and metastasis

• The nanoparticles stepwise target tumor cells’ mitochondria to alleviate side effects. • In situ mitochondrial damage and antitumor immune response are achieved efficiently. • Rational precise combination therapy can inhibit tumor recurrence and metastasis. Photothermal therapy (PTT) is a promising therapeutic modality, but still faces some potential limitations, such as unfavorable thermal damage to normal tissues, limited light penetration depth, unpredictable tumor recurrence and metastasis. Additionally, mitochondria play a key role in maintaining multiple cellular functions, whereas displaying fragile thermal sensitivity. Herein, we report on the fabrication of an immunomodulator (R848)-loaded polymeric nanoparticles, R848@cRGD-PDCS, which can spontaneously target mitochondria of tumor cells that benefits from native mitochondria-targeting near-infrared (NIR) light-absorbing moieties. Upon NIR laser irradiation, photothermal-induced mild hyperthermia can efficiently damage the mitochondria in primary tumor cells, promoting efficient release of tumor-associated antigens. Combined with the immune checkpoint blockade (ICB), tumor-mediated immunosuppression can be alleviated, thus the activated antitumor immune response can effectively suppress distant tumors and overcome tumor recurrence and metastasis, achieving long-term antitumor immune memory to inhibit tumor metastasis. Current native mitochondrial targeting phototherapeutic nanoparticles potentiated with immunotherapy are promising for precision translational medicine.