PAD4 Inhibitor‐Loaded Layered Double Hydroxide Nanosheets as a Multifunctional Nanoplatform for Photodynamic Therapy‐Mediated Tumor Metastasis Treatment

Abstract Photodynamic therapy (PDT) is demonstrated to be effective in inducing antitumor immune responses for tumor metastasis treatment. However, tumor hypoxia, inferior tissue penetration of light, and low singlet oxygen (¹O₂) quantum yield significantly hamper the efficacy of PDT, thus weakening its immune function. Moreover, PDT‐mediated neutrophil extracellular traps (NETs) formation can further reduce the therapeutic effectiveness. Herein, the use of defect‐rich CoMo‐layered double hydroxide (DR‐CoMo‐LDH) nanosheets as a carrier to load a typical peptidyl arginine deiminase 4 inhibitor, i.e., YW4‐03, to construct a multifunctional nanoagent (403@DR‐LDH) for PDT/immunotherapy, is reported. Specifically, 403@DR‐LDH inherits excellent ¹O₂ generation activity under 1550 nm laser irradiation and improves the half‐life of YW4‐03. Meanwhile, 403@DR‐LDH plus 1550 nm laser irradiation can stimulate immunogenic cell death to promote the maturation of dendric cells and activation/infiltration of T cells and significantly downregulate H3cit protein expression to inhibit NETs formation, synergistically promoting the antitumor metastasis effect. Taken together, 403@DR‐LDH can kill cancer cells and inhibit tumor growth/metastasis under 1550 nm laser irradiation. Single‐cell analysis indicates that 403@DR‐LDH can regulate the ratio of immune cells and immune‐related proteins to improve the tumor immune microenvironment, showing strong efficacy to inhibit the tumor growth, metastasis, and recurrence.