Self-Splittable Transcytosis Nanoraspberry for NIR-II Photo-Immunometabolic Cancer Therapy in Deep Tumor Tissue

Cancer photo-immunotherapy (CPIT) as an ideal strategy can rapidly release hostile signals by appropriate dosage of focal laser irradiation to unmask primary tumor immunogenicity and can activate adaptive immunity to control distant metastases. However, many factors, including disordered immunometabolism, poor penetration of photothermal agents and immuno-regulators, inadequate laser penetration into the deep tumor region, restrict the therapeutic outcomes of CPIT. Here, a second near-infrared window (NIR-II) photo-immunometabolic cancer therapy (PICT) by a programmed raspberry-structured nanoadjuvant (PRN^MT ) is presented that can potentiates efficient immunogenic cell death (ICD) in deep tumor tissue and alleviates immunometabolic disorder. The PRN^MT is architected through self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor modified small-sized CuS nanoparticles (CuS₅ ) and tumor microenvironment (TME) responsive cationized polymeric matrix. The TME can trigger the splitting and surface cationization of PRN^MT into small cationized CuS₅ that feature high transcytosis potential and TME immunometabolic regulation. Upon NIR-II irradiation, CuS₅ induce homogeneous ICD and release immunometabolic regulator in deep tumor tissues, which ameliorates IDO-1 mediated immunometabolic disorder and further suppresses regulatory T cells infiltration. PRN^MT mediated PICT effectively delays the primary murine mammary carcinoma 4T1 tumor growth and inhibits the lethal pulmonary metastasis in combination with programmed cell death protein 1 (PD1) blockade.