Hypoxia-modulatory nanomaterials to relieve tumor hypoxic microenvironment and enhance immunotherapy: Where do we stand?

The past several years have witnessed the blooming of emerging immunotherapy, as well as their therapeutic potential in remodeling the immune system. Nevertheless, with the development of biological mechanisms in oncology, it has been demonstrated that hypoxic tumor microenvironment (TME) seriously impairs the therapeutic outcomes of immunotherapy. Hypoxia, caused by Warburg effect and insufficient oxygen delivery, has been considered as a primary construction element of TME and drawn tremendous attention in cancer therapy. Multiple hypoxia-modulatory theranostic agents have been facing many obstacles and challenges while offering initial therapeutic effect. Inspired by versatile nanomaterials, great efforts have been devoted to design hypoxia-based nanoplatforms to preserve drug activity, reduce systemic toxicity, provide adequate oxygenation, and eventually ameliorate hypoxic-tumor management. Besides these, recently, some curative and innovative hypoxia-related nanoplatforms have been applied in synergistic immunotherapy, especially in combination with immune checkpoint blockade (ICB), immunomodulatory therapeutics, cancer vaccine therapy and immunogenic cell death (ICD) effect. Herein, the paramount impact of hypoxia on tumor immune escape was initially described and discussed, followed by a comprehensive overview on the design tactics of multimodal nanoplatforms based on hypoxia-enabled theranostic agents. A variety of nanocarriers for relieving tumor hypoxic microenvironment were also summarized. On this basis, we presented the latest progress in the use of hypoxia-modulatory nanomaterials for synergistic immunotherapy and highlighted current challenges and plausible promises in this area in the near future. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy, emerging as a novel treatment to eradicate malignant tumors, has achieved a measure of success in clinical popularity and transition. However, over the last decades, hypoxia-induced tumor immune escape has attracted enormous attention in cancer treatment. Limitations of free targeting agents have paved the path for the development of multiple nanomaterials with the hope of boosting immunotherapy. In this review, the innovative design tactics and multifunctional nanocarriers for hypoxia alleviation are summarized, and the smart nanomaterial-assisted hypoxia-modulatory therapeutics for synergistic immunotherapy and versatile biomedical applications are especially highlighted. In addition, the challenges and prospects of clinical transformation are further discussed.

Chitosan-Coated Diatom Silica as Hemostatic Agent for Hemorrhage Control.

Uncontrolled hemorrhage leads to high death risk both in military and civilian trauma. Current hemostatic agents still have various limitations and side effects. In this study, natural diatom silica obtained from diatomite and diatom culture was purified and developed for hemorrhage control. To improve the biocompatibility and hemostatic performance of diatom silica, a series of chitosan-coated diatom (CS-diatom) was developed. The composition of CS-diatom prepared was optimized by in vitro hemocompatibility and blood coagulation evaluation for that prepared with 0.5%, 1%, 3%, and 5% chitosan. The results demonstrated that the CS-diatom prepared with 1% chitosan exhibited favorable biocompatibility (hemolysis ratio < 5%, no cytotoxicity to MEFs), great fluid absorbility (24.39 ± 1.53 times the weight of liquid), and desirable hemostasis effect (351 ± 14.73 s at 5 mg/mL, 248 ± 32.42s at 10 mg/mL). Further blood coagulation mechanism study indicated that CS-diatom could provide an ideal interface to induce erythrocyte absorption and aggregation, along with activating the intrinsic coagulation pathway and thus accelerated blood coagulation. Benefitting from the multiple hemostatic performances, CS-diatom showed the shortest clotting time (98.34 ± 26.54 s) and lowest blood loss (0.31 ± 0.11 g) in rat-tail amputation model compare to diatomite and diatom as well as gauze and commercial QuikClot zeolite. The results evidenced that the CS-diatom was a safe and effective hemostatic agent and provided a new understanding of nonsynthetic mesoporous materials for hemorrhage control.