Cyclic enhancement of hypoxic microenvironment via an intelligent nanoamplifier for activated NIR-II fluorescence/photoacoustic imaging-guided precise synergistic therapy

Tumor microenvironment (TME)-activated theranostics is a promising strategy to effectively identify small lesions, improve antitumor efficacy, and reduce the risk of undesired side effects. Hypoxia, as a common characteristic of TME, can serve as a preferred site for stimulus-dependent activation; however, tumor-hypoxia levels in various developmental stages exhibit different characteristics, severely limiting the response sensitivity. Herein, a circulating self-reinforcing hypoxic nanoamplifier (CGH NAs) is developed that utilizes a dual-chain reaction process (internal regulation, internal regulation) to achieve precise activation of NIR-II FL/photoacoustic (PA) imaging-guided synergistic therapy. Inspired by the positive correlation of nitroreductase (NTR) with hypoxia, the CGH NAs encapsulate CQ4T and GOx into NTR-sensitive hyaluronic acid-nitroimidazole (HA-NI) shell via a self-assembly approach, enabling aggregation-caused NIR-II FL quenching and tumor-accurate delivery. When CGH NAs efficiently accumulated in the tumor region, the intensive local NTR reduced hydrophobic –NO(2) to hydrophilic –NH(2), which lead to disassembly of CGH NAs. The released GOx could consume O(2) (internal regulation) and glucose to cut off the energy supply, inducing tumor-starvation therapy; generate gluconic acid and H(2)O(2) (oxidative stress). Meanwhile, the released CQ4T promoted rapid recovery of NIR-II FL signals for imaging-guided PDT, which could simultaneously deplete intratumoral O(2) (external stimulation). Remarkably, the strengthened tumor-hypoxia levels in turn accelerated the NTR-responsive degradation of the CGH NAs, thereby achieving high-efficiency theranostic.