Sequential photoactivatable metal-phenolic network enables spatiotemporally deep-tissue photoacoustic imaging-guided programmed photothermal therapy

High spatiotemporal precision in targeted drug delivery and controlled activation remains a significant challenge in cancer theranostics due to the complex tumor microenvironment (TME). Here, we introduce a sequential near-infrared (NIR) light-assisted, TME-responsive nanoplatform (GA/cypate@MP-Pap) that employs a two-step NIR light activation strategy for in situ self-assembly of a metal-phenolic network, enabling deep-tissue photoacoustic (PA) imaging and enhanced photothermal therapy (PTT). Upon initial NIR light exposure, the nanoplatform activates thermophilic enzymes, triggering selective degradation of the tumor stroma, which significantly enhances its penetration into deeper tumor regions. Within the TME, the nanoplatform disassembles, releasing Mn2+ and GA that chelate to form photothermally potent metal-phenolic networks. A subsequent NIR light exposure then amplifies PA signals and PTT efficacy, precisely targeting tumor cells with minimized effects on normal tissues. This dual NIR light-triggered, enzyme-activated strategy provides a novel approach for imaging-guided cancer therapy with high precision both spatially and temporally.