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The development of new organic nanoagents with extremely high photothermal conversion efficiency and good biocompatibility has gained considerable attention in the area of photothermal cancer therapy. In this work, we designed and synthesized a new porphyrin polymer (P-PPor) with donor-acceptor (D-A) structure. P-PPor displayed intense absorbance in the near-infrared (NIR) region with the maximum peak around at 850 ​nm. Under excitation of 808 ​nm, P-PPor demonstrated the significant fluorescence in the NIR-II region ( λ max ​= ​1015 ​nm), with the fluorescence quantum yield of 2.19%. Due to the presence of hydrophilic PEG chains and hydrophobic alkyl chains in the conjugated skeleton, the amphiphilic P-PPor could self-assemble into the nanoparticles (P-PPor NPs) with good dispersibility in water and enhanced absorption in the NIR region. Moreover, P-PPor NPs exhibited quenched fluorescence because of the aggregation-caused quenching (ACQ) effect, resulting in the distinct photothermal effect. The photothermal conversion efficiency (PCE) of P-PPor NPs was measured as 66% under 808 ​nm laser irradiation, higher than most of PTT agents. The remarkable photothermal effect of P-PPor NPs was further demonstrated in vitro and in vivo using 4T1 tumor mode. Meanwhile, the NIR-II fluorescence imaging in vivo indicated the high distribution of P-PPor NPs in tumor site. These results suggested that P-PPor NPs could effectively damage the cancer cells in mice under 808 ​nm laser irradiation, and did not cause any obvious side effects after phototherapy. Thus, P-PPor NPs could be used as a potential agent in photothermal cancer therapy with high effectiveness and safety.

Combinatorial photothermal and immunotherapy have demonstrated great potential to remove primary tumors, suppress metastases, and prevent tumor recurrence. However, this strategy still confronts with many limitations, such as complex components, sophisticated construction and inadequate therapeutic e cacy. In this work, we develop small molecules of porphyrin derivatives (PPor) which can selfassemble into monodispersed nanoparticles without supplement of any other ingredients or surfactants.The formed PPor nanoparticles (PPor NPs) exhibit highly photothermal conversion efficiency of 70% and NIR-II luminous abilities originated from the strong intramolecular charge transfer (ICT) effect of D-A structure under 808 nm laser irradiation, thus achieving NIR-II uorescence imaging guided photothermal therapy (PTT) against primary tumor with a high cure rate. More importantly, tumor-associated antigens (TAAs) together with damage-associated molecular patterns (DAMPs) released from PTT-treated cancer cells are proved to elicit immune responses in some degree. After combination with programmed cell death-1 (PD-1) antibody, a robust systematic antitumor immunity are generated to restrain both primary and abscopal tumors growth, prolong survival, prevent pulmonary metastasis on an aggressive 4T1 murine breast tumor model. Thus, this study provides a promising therapeutic paradigm with porphyrin derivatives nano-assembly as phototheranostic agents for the treatment of aggressive tumor with high e ciency.

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