Recent advances in mechanical force-responsive drug delivery systems.

Mechanical force responsive drug delivery systems (in terms of mechanical force induced chemical bond breakage or physical structure destabilization) have been recently explored to exhibit a controllable pharmaceutical release behaviour at a molecular level. In comparison with chemical or biological stimulus triggers, mechanical force is not only an external but also an internal stimulus which is closely related to the physiological status of patients. However, although this mechanical force stimulus might be one of the most promising and feasible sources to achieve on-demand pharmaceutical release, current research in this field is still limited. Hence, this tutorial review aims to comprehensively evaluate the recent advances in mechanical force-responsive drug delivery systems based on different types of mechanical force, in terms of direct stimulation by compressive, tensile, and shear force, or indirect/remote stimulation by ultrasound and a magnetic field. Furthermore, the exciting developments and current challenges in this field will also be discussed to provide a blueprint for potential clinical translational research of mechanical force-responsive drug delivery systems.

Mitochondria targeted composite enzyme nanogels for synergistic starvation and photodynamic therapy.

Mitochondria, as the energy factory of cells, often maintain a high redox state, and play an important role in cell growth, development and apoptosis. Therefore, the destruction of mitochondrial redox homeostasis has now become an important direction for cancer treatment. Here, we design a mitochondrial targeting composite enzyme nanogel bioreactor with a circulating supply of O2 and H2O2, which is composed of mitochondrial target triphenylphosphine (TPP), natural enzymes glucose oxidase (GOX) and catalase (CAT), and protoporphyrin IX (PpIX). The nanogel can effectively increase the stability of the natural enzymes, and its size of about 65 nm makes them close in space, which greatly improves their cascade catalytic efficiency and safety. Under the action of target TPP, the system can accurately target the mitochondria of breast cancer 4T1 cells, catalyze intracellular glucose to generate H2O2 through GOX, and H2O2 is further used as a catalytic substrate for CAT to generate O2. This O2 can not only further improve the catalytic efficiency of GOX, but also provide raw materials for the production of ROS in PDT, which can effectively destroy the mitochondria of cancer cells, thereby causing tumor cell apoptosis. Compared with GOX alone, thanks to the close spatial position of the composite enzymes, the composite enzyme nanogel can quickly consume the highly oxidative H2O2 produced by GOX, thereby showing better safety to normal cells. In addition, the composite enzyme group under light showed excellent antitumor effects by combining starvation therapy and PDT under adequate oxygen supply in animal experiments. In general, this composite enzyme nanogel system with good stability, high safety and excellent cascade catalytic efficiency opens a new way for the development of safe and efficient cancer therapeutics.

The Translational Application of Hydrogel for Organoid Technology: Challenges and Future Perspectives.

Human organoids mimic the physiology and tissue architecture of organs and are of great significance for promoting the study of human diseases. Traditionally, organoid cultures rely predominantly on animal or tumor-derived extracellular matrix (ECM), resulting in poor reproducibility. This limits their utility in for large-scale drug screening and application for regenerative medicine. Recently, synthetic polymeric hydrogels, with high biocompatibility and biodegradability, stability, uniformity of compositions, and high throughput properties, have emerged as potential materials for achieving 3D architectures for organoid cultures. Compared to conventional animal or tumor-derived organoids, these newly engineered hydrogel-based organoids more closely resemble human organs, as they are able to mimic native structural and functional properties observed in-situ. In this review, recent developments in hydrogel-based organoid culture will be summarized, emergent hydrogel technology will be highlighted, and future challenges in applying them to organoid culture will be discussed.

Thermogelling chitosan-based polymers for the treatment of oral mucosa ulcers.

Current treatments for oral mucosa-related ulcers use drugs to relieve pain and promote healing, but rarely consider drug resistance to bacterial infection in the microenvironment of the oral cavity or the prevention of bleeding from gingival mucosa ulcers. We herein report an injectable, thermogelling chitosan-based system to address these concerns. An aqueous solution of chitosan-based conjugates (chitosan-g-poly(N-isopropylacrylamide) [CS-g-PNIPAAM] including 1a [CS-g-PNIPAAM with less PNIPAAM] and 1b [CS-g-PNIPAAM with more PNIPAAM], and chitosan-g-poly(N-isopropylacrylamide)-g-polyacrylamide [CS-g-PNIPAAM-g-PAM] 3) could reversibly form semi-solid gels at physiological temperatures for easy application to oral cavity ulcer sites by injection. The chitosan-based conjugate thermogels prepared could inhibit both Gram-positive and Gram-negative bacteria and the two with higher chitosan and poly(N-isopropylacrylamide) contents (1a and 1b) promoted proliferation of gingival fibroblasts in vitro. These two thermogels also exhibited improved blood clotting in an in vivo rat study. Thermogels 1a and 1b effectively promoted ulcer healing and shortened ulcer healing times in an oral gingival mucosa ulcer model using Sprague Dawley (SD) rats. These thermogels showed no obvious toxicity to the main organs of SD rats undergoing gingival ulcer treatment. These results suggest that this antibacterial biomaterial could be a promising injectable therapeutic agent for the treatment for oral mucosa ulcers.