Rational Design of a Smart Phototheranostic Nanoagent Based on a NIR-II-Conjugated Polymer for Highly Tumor-Specific Multimodal Imaging-Guided Synergistic Therapy.

Exploration of precise cancer therapy promotes the development of tumor microenvironment (TME)-responsive imaging-guided phototheranostic nanoagents. Currently, near-infrared-II (NIR-II, 1000-1700 nm) phototheranostic nanoagents are highly desired for deep and high-fidelity imaging. Besides, nontumor-specific imaging and some inherent physiological conditions in TME have severely hindered the enhancement of therapeutic efficacy. Herein, two amphiphilic conjugated polymers (CPs), P1 and P2, were designed with the backbone containing electron-deficient diketopyrrolopyrrole (DPP) as the acceptor (A) and doped electron-rich fluorene as the donor (D). As the doping ratio of fluorene was tuned from 0 to 0.2, P2 was obtained as an "always-on" probe with excellent NIR-II photoacoustic/fluorescence imaging (PAI/FLI) capability as well as photodynamic/photothermal therapy (PDT/PTT) efficacy. Then, a smart phototheranostic nanoagent P2@MnO2@HA-SS-BFVPBT (PMH) based on the combination of "always-on" and "turn-on" probes was rationally designed for dual-FL/PA imaging-guided synergistic PDT/PTT/chemodynamic therapy (CDT). In PMH, the fluorescence of BFVPBT, a conjugated oligomer linked to the side chains of hyaluronic acid (HA) by cystamine containing disulfide (-SS-) bonds, was quenched by MnO2 via an inner filter effect. After the tumor-targeting delivery of PMH via HA, the degradation of HA-SS-BFVPBT and MnO2 was triggered by overexpressed hyaluronidase (HAase), glutathione (GSH), and H2O2 in TME, leading to the "turn-on" BFVPBT fluorescence and the generation of in situ O2 and Mn2+ along with the consumption of GSH, and thereby synergistically enhancing the efficacy of PDT and Fenton-like reaction-mediated CDT by modulating TME. Moreover, the "always-on" NIR-II photoacoustic/fluorescence intensity and the "turn-on" fluorescence intensity at the tumor site can reach up to about seven times the background intensity, achieving effective dynamic monitoring of the nanoagent distribution in vivo. Thus, this smart nanoagent simultaneously combined active tumor targeting and TME response for highly tumor-specific multimodal imaging-guided synergistic PDT/PTT/CDT, providing a simple and universal strategy for enhancing the precision and efficiency of phototheranostics.