Dual-triggered in situ assembly of Mn-polyphenol networks in tumor cells for enhanced manganese retention and oxidative stress amplification.
Chemodynamic therapy (CDT), which harnesses the tumor microenvironment (TME), holds great promise for tumor treatment by generating reactive oxygen species (ROS) in situ. The efficacy of CDT relies on the efficient release and retention of transition-metal ions at the tumor site. Metal-phenolic networks (MPNs) provide an appealing platform for immobilizing metal ions within coordination architectures. Nevertheless, conventionally pre-assembled MPNs frequently suffer from inadequate targeted delivery. Here, we report an intelligent nanoplatform, DHU-MG@MnSiP, that unites dual TME activation with controlled in-situ coordination assembly. The platform comprises an acid-responsive Mn-doped hollow mesoporous silica encapsulating a hypochlorous acid (HOCl)-activatable polyphenolic pro-ligand (MB-GA). Under mildly acidic conditions, Mn ions and MB-GA are co-released. Subsequent HOCl cleavage of MB-GA liberates gallic acid (GA), driving the formation of a Mn-GA network and enabling regulated in-situ self-assembly. This weak coordination architecture increases local Mn retention and sustains a GA-assisted Mn(II)/Mn(III) redox cycle. The network dissociates in lysosomes to release Mn ions, thereby potentiating CDT. Concurrently, the HOCl-triggered release of methylene blue (MB) enables photodynamic therapy (PDT) to generate ROS, achieving synergistic CDT/PDT. This dual-trigger strategy provides precise activation and oxidative amplification within the TME, translating into robust in vivo antitumor effects. By shifting the construction of the active agent from pre-assembly in vitro to controlled in-situ formation at the lesion site, the present work exemplifies a programmable strategy that enables effective regulation of metal-ion retention and release.