Targeting and Microenvironment-Activated Nanoreactor for Diabetic Chronic Wound Healing via Multienzyme Cascade Reactions

The development of cell-like nanoreactors with the ability to initiate biocatalytic cascades under special conditions holds tremendous potential for therapeutic applications. Herein, conformationally gated nanoreactors that respond to the acidic microenvironment of infected diabetic wounds were developed by cucur[8]bituril (CB[8])-based supramolecular assembly. The bioinspired nanoreactors exhibit not only self-regulated permeability and selectivity to control internal enzyme activities by substance exchange but also distinct binding specificities toward Gram-positive and Gram-negative bacteria via noncovalent modification with different ligands. The encapsulation of glucose oxidase (GOx), Fe 3 O 4 nanozyme, and l -arginine ( l -Arg) into the nanocarriers enables intelligent activation of multienzyme cascade reactions upon glucose (Glu) uptake to produce gluconic acid (GA) and hydrogen peroxide (H 2 O 2 ), which is further converted into highly toxic hydroxyl radicals (·OH) for selective antibacterial activity. Moreover, acidic H 2 O 2 promotes the oxidization of l -Arg, leading to the release of nitric oxide (NO). Consequently, this nanoreactor provides a multifunctional and synergistic platform for diabetic chronic wound healing by combining enzyme dynamic therapy with NO gas therapy to combat bacterial infections and inflammation under high blood Glu levels.

能够在特殊条件下启动生物催化级联的类细胞纳米反应器的开发在治疗应用方面具有巨大的潜力。在此，通过基于 cucur[8]bituril (CB[8]) 的超分子组装开发了对感染糖尿病伤口的酸性微环境做出反应的构象门控纳米反应器。仿生纳米反应器不仅表现出自我调节的渗透性和选择性，通过物质交换控制内部酶活性，而且通过不同配体的非共价修饰，对革兰氏阳性和革兰氏阴性细菌具有不同的结合特异性。将葡萄糖氧化酶（GOx）、Fe 3 O 4 纳米酶和l-精氨酸（l-Arg）封装到纳米载体中，能够智能激活葡萄糖（Glu）摄取后的多酶级联反应，产生葡萄糖酸（GA）和过氧化氢（H 2 O 2 ），进一步转化为剧毒的羟基自由基（·OH），从而实现选择性抗菌活性。此外，酸性H 2 O 2 促进l-Arg的氧化，导致一氧化氮(NO)的释放。因此，该纳米反应器通过将酶动力疗法与一氧化氮气体疗法相结合来对抗高血糖水平下的细菌感染和炎症，为糖尿病慢性伤口愈合提供了一个多功能和协同平台。