Chemo-phototherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. However, the complex tumor microenvironment restricts the penetration depth of chemo-phototherapy agents in the tumor region. Here, biodegradable amphiphilic gelatin (AG) wrapped nanocomposite (PRDCuS@AG) composed of doxorubicin and copper sulfide (CuS)-loaded dendrimer is designed for deep tumor chemo-phototherapy. PR in PRDCuS@AG represents arginine-conjugated polyamidoamine dendrimer. PRDCuS@AG can rapidly biodegrade into PRDCuS by matrix metalloproteinases under near-infrared light irradiation. The resulted PRDCuS harbors dual cell-tissue penetration ability, which can effectively penetrate deep into the tumor tissue. In particular, PRDCuS@AG achieves photoacoustic imaging-guided synergistic chemo-phototherapy with 97% of tumor inhibition rate. Moreover, PRDCuS@AG can further degrade into 3 nm ultrasmall CuS, which can be eliminated from the body after treatment to avoid side effects. This strategy provides an insight that the development of chemo-phototherapy agents with high penetration ability to overcome the limitation of current deep tumor therapy.

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