A metal protoporphyrin-induced nano-self-assembly for potentiating photothermal therapy by depleting antioxidant defense systems

• Zinc protoporphyrin induces the self-assembly of multiple Cu 2-x S nanoparticles. • Zinc protoporphyrin resists the intracellular HSP expression in PTT. • Cu 2-x S nanoparticle acts as an effective photothermal agent in NIR-II window. • The integration of two agents achieves a synergistic anti-tumor effect. Nanomaterial-mediated low-temperature photothermal therapy (PTT) by integrating photothermal agent and heat shock proteins (HSPs) inhibitor holds great potential application in antitumor treatment. A nanoplatform performing improved therapeutic effect that constructed at large scale with green synthesis, high drug loading efficiency, high drug loading capacity, and low cost is highly desired. Herein, we report a metal protoporphyrin-induced self-assembling nanoagent (ZCNA) by integration of hydrophobic Cu 2-x S nanoparticles and zinc protoporphyrin (ZnPP) via a facile volatilization-driven approach without using of any additional stabilizing or carrier material. This nanoagent is featured with simplified preparation, high ZnPP loading efficiency, high ZnPP loading capacity, and excellent biocompatibility. ZCNA acts as a contrast agent for photoacoustic imaging and a photothermal agent for PTT. Meanwhile, the released ZnPP from ZCNA could resist the expression of an important type of HSPs, heme oxygenase-1 (HO-1), and thereby deplete the antioxidant defense systems of tumor cells during PTT, which is responsible for the significantly enhanced antitumor effect of ZCNA in low-temperature PTT in comparison with the non-ZnPP containing Cu 2-x S-based nanoagent both in vitro and in vivo . Overall, the ingeniously constructed ZCNA can be an effective theranostic platform with photoacoustic imaging capability and synergistic antitumor effect to advance the clinical translation of low-temperature PTT-based tumor therapy.