Cascades catalyzed lactic acid depletion coordinated with photothermal therapy for enhanced cancer immunotherapy

A large amount of lactate accumulated in the tumor tissues plays an important role in tumor angiogenesis, recurrence, metastasis, drug resistance and immunosuppression. However, there is a lack of a simple and efficient lactate depletion strategy. Herein, a red blood cell membrane (mRBC)-camouflaged polydopamine (PDA)-coated dendritic mesoporous silicon nanoparticle (DMSN) was constructed for the delivery of lactate oxidase (LOX) to achieve coordinated catalytic consumption of intracellular and extracellular lactate and modulation of immunotherapy (denoted as DPLM). Due to the encapsulation of the mRBC, the DPLM could achieve long circulation in the blood and gradually accumulate into the tumor tissues within 8 h. The PDA which possessed catalase-like nature could catalyze the decomposition reaction of H 2 O 2 in hypoxic tumor tissue, therefore providing oxygen for LOX to oxidize extracellular lactate. Meanwhile, with the help of the photothermal conversion ability of PDA, the laser-trigged low-temperature photothermal effect on DPLM could cause the endosomal escape, which facilitated the delivery of LOX into cytoplasm to deplete intracellular lactate. In addition, due to the photothermal effect, tumor cells could release immune signals that promoted immune cells infiltration into tumor tissues. This study provides an innovative LOX delivery system to regulate tumor acid environment and relieve immunosuppression.