Breaking‐Down Tumoral Physical Barrier by Remotely Unwrapping Metal‐Polyphenol‐Packaged Hyaluronidase for Optimizing Photothermal/Photodynamic Therapy‐Induced Immune Response

Abstract The therapy of solid tumors is often hindered by the compact and rigid tumoral extracellular matrix (TECM). Precise reduction of TECM by hyaluronidase (HAase) in combination with nanotechnology is promising for solid tumor therapeutics, yet remains an enormous challenge. Inspired by the treatment of iron poisoning, here a remotely unwrapping strategy is proposed of metal‐polyphenol‐packaged HAase (named PPFH) by sequentially injecting PPFH and a clinically used iron‐chelator deferoxamine (DFO). The in situ dynamic disassembly of PPFH can be triggered by the intravenously injected DFO, resulting in the release, reactivation, and deep penetration of encapsulated HAase inside tumors. Such a cost‐effective HAase delivery strategy memorably improves the subsequent photothermal and photodynamic therapy (PTT/PDT)‐induced intratumoral infiltration of cytotoxic T lymphocyte cells and the cross‐talk between tumor and tumor‐draining lymph nodes (TDLN), thereby decreasing the immunosuppression and optimizing tumoricidal immune response that can efficiently protect mice from tumor growth, metastasis, and recurrence in multiple mouse cancer models. Overall, this work presents a proof‐of‐concept of the dynamic disassembly of metal‐polyphenol nanoparticles for extracellular drug delivery as well as the modulation of TECM and immunosuppressive tumor microenvironment.