Biodegradable Nickel Phosphide Mediated Adenosine Metabolism and Hippo Pathway Inhibition for Synergistic Photothermal Immunotherapy

The abnormal accumulation of adenosine (Ado) can produce an immunosuppressive microenvironment in tumors. The increase in Ado can activate the Hippo signaling pathway for upregulating Yes-associated protein (YAP) expression and promoting the growth of tumors. Herein, resveratrol-loaded and poly(acrylic acid)-coated biodegradable nickel phosphide (NPRA) nanoparticles (NPs) were developed to improve therapeutic efficacy through simultaneously reducing Ado levels and inhibiting YAP expression. The photothermal performance of NPRA NPs can first promote the recruitment of cytotoxic T lymphocytes (CTLs). Then, with the help of the acidic tumor microenvironment and photothermal property of NPRA, phosphate ions (PO 4 3– ) and resveratrol were released. The released PO 4 3– can reduce Ado levels and enhance CTL recruitment. Meanwhile, the proliferation and growth of cancer cells are suppressed through the synergistic effect of PO 4 3– -induced autophagy inhibition and resveratrol-triggered YAP downregulation. In vitro and in vivo assessments show that NPRA NPs could be effectively degraded and release resveratrol, thus decreasing Ado levels and YAP expression, exhibiting good cell-killing and tumor-eliminating effect. As a result, the development of NPRA NPs paves the way for synergistic tumor photoimmunotherapy by combining photothermal therapy, drug delivery, and tumor microenvironment regulation.