**Background:** Surgery is the primary treatment for melanoma, but incomplete resection often leads to tumor recurrence (>90% of cancer deaths) and metastasis. Additionally, large-scale skin defects after surgery cause delayed wound healing due to hypoxia. Photodynamic therapy (PDT) can kill residual tumor cells but is limited by hypoxia, which also activates HIF-1α-driven metastasis and impairs wound healing. This study aimed to develop a sprayable hydrogel that continuously supplies oxygen via photosynthetic cyanobacteria to simultaneously prevent tumor recurrence/metastasis and promote wound healing.
**Methods:** The HIL@Z nanodrug was synthesized by encapsulating indocyanine green (ICG) and L-arginine (L-Arg) into ZIF-8 nanoparticles, then coating with hyaluronic acid (HA) for CD44-targeted delivery. The sprayable hydrogel (HIL@Z/P/H) was formed by simultaneously spraying CaCl₂ solution and alginate solution containing HIL@Z nanodrug and photosynthetic cyanobacteria (PCC 7942). In vitro, B16F10 melanoma cells were used to assess cellular uptake, oxygenation (Ru(dpp)₃Cl₂ probe), ROS/NO/RNS generation (DCFH-DA, DAF-FM DA, DHR), GSH depletion (ThiolTracker Violet), and cytotoxicity (alamar blue, live/dead, flow cytometry). In vivo, an incomplete tumor resection model (~95% tumor removal) was established in C57BL/6 mice. Mice received HIL@Z/P/H spray followed by Red laser (635 nm, 1.0 W/cm², 30 min) and NIR laser (808 nm, 1.5 W/cm², 10 min) on days 1, 3, and 5. Tumor recurrence, wound healing, survival, and lung metastasis were monitored over 14–42 days. A separate full-thickness skin defect model (8 mm) was used to evaluate wound healing alone.
**Key Results:** HIL@Z nanoparticles had a hydrodynamic diameter of ~218 nm, zeta potential of −22.3 mV, and pH-responsive drug release (79.8% ICG released at pH 5.5 vs. 6.8% at pH 7.4 after 12 h). Under NIR irradiation, HIL@Z generated ROS (76.5% DPBF consumed in 10 min at 1.5 W/cm²), NO (5.8 µM after 10 min), and ONOO⁻. PCC 7942 in the hydrogel produced O₂ continuously for 15 days without decay. In vitro, HIL@Z/P/H+Red+NIR reduced B16F10 cell viability to 19.0% (vs. 33.4% without Red) and increased late apoptosis/necrosis (66.76% late apoptosis + 4.19% necrosis). Intracellular ROS, NO, and ONOO⁻ levels were highest in the HIL@Z/P/H+Red+NIR group, while GSH was nearly depleted. HIF-1α and MMP-9 protein expression were reduced by ~60% and ~80%, respectively, compared to control. In vivo, the HIL@Z/P/H+Red+NIR group showed the smallest tumor volume and weight on day 14, with 80% survival at 42 days (vs. 0% in control). Wound closure reached ~98.9% on day 12 (vs. ~19.3% in control). H&E and TUNEL staining confirmed extensive tumor cell apoptosis/necrosis, and Ki67 staining showed minimal proliferation. No lung metastatic nodules were observed in the HIL@Z/P/H+Red+NIR group, while other groups had distinct nodules. Immunohistochemistry revealed significantly higher VEGF, CD31, and α-SMA expression and lower HIF-1α in the treatment group. Body weight, blood biochemistry, and histology of major organs showed no toxicity.
**Clinical Implications:** This study presents a novel, portable, and sprayable therapeutic hydrogel that addresses two major postsurgical challenges in melanoma: tumor recurrence/metastasis and wound healing. By providing long-lasting oxygen through photosynthesis, the system overcomes hypoxia-driven resistance to PDT, inhibits HIF-1α-mediated metastasis, and accelerates wound healing via enhanced angiogenesis. The dual-action approach—disrupting redox homeostasis in tumor cells while promoting tissue regeneration—offers a promising adjuvant strategy for postsurgical cancer therapy. The biocompatibility and ease of application (sprayable, in situ gelation) suggest potential for clinical translation, though further studies in larger animal models and humans are needed.