Photothermal therapy (PTT) holds potential as a noninvasive cancer treatment but is challenged by limited tissue penetration due to physiological barriers. Here, we report that conditional extracellular matrix proteolysis augments deep-tissue PTT using a near-infrared (NIR)-II light-activatable biomineralized material. We demonstrate specific photothermic manipulation of biomineralized nanoarchitectures by encapsulating gold nanostars and the thermozyme bromelain into nanoframework for spatially controlled tumor stroma remodeling. This transformable nanomedicine allows active transport and effective particle accumulation via stromal-targeting ligand and subsequent therapeutics release in response to microenvironment, which exposes thermozyme and photothermal agent with spiky surface and smaller size that can facilitate cellular internalization and penetration. Notably, light-initiated hyperthermia-activated thermozyme induces in situ degradation of key extracellular matrix scaffold for tumor-specific stroma barrier breaking, and thus synergizes with NIR-II thermoplasmonics to access cancer cells at deep sites. This approach significantly enhances tumor accumulation and penetration to potentiate photothermal ablation in different tumor models, showing inhibitory rate up to 98.9%. Compared to NIR-II PTT incapable of stroma breakdown, our method leveraging NIR-II thermoplasmonics and thermozyme achieves folds increase in antitumor efficacy using murine model. These findings may facilitate efforts to design spatiotemporal controllable agents for safe and effective therapy.

Metastasis remains the primary cause for mortality of breast cancer. Despite advances in current therapeutic agents, patients with metastatic breast cancer still have poor prognoses. Tumor hypoxia, a key microenvironment factor, is emerging as an attractive target to prevent metastasis and is also involved with resistance to phototherapy. Here, we show an effective nanotherapeutic approach based on manganese dioxide-coated polydopamine nanocarriers to trigger robust anti-tumor and anti-metastasis responses against metastatic breast cancer by supplemental oxygenation and multimodal imaging-guided phototherapies. In cancer cells, the produced oxygen by the developed nanoplatform decreases the expression of hypoxia-inducible factors 1α to inhibit tumor metastasis, and enhances the efficacy of photodynamic therapy. This nanotherapeutic approach enables the combined photodynamic/ photothermal treatments with great inhibition on cell migration and invasion in vitro. Moreover, the nanotherapeutics effectively suppresses primary tumor progress and inhibits lung metastasis in vivo in a breast cancer mouse model with satisfying biosafety. This study suggests that the tumor hypoxia-targeting nanotherapeutics have great potential for preventing and treating metastatic cancers.