Abstract：
Reactive oxygen species (ROS) are widely considered to the effective therapeutics for fighting bacterial infections especially those associated with biofilm. However, biofilm microenvironments including hypoxia, limited H2O2, and high glutathione (GSH) level seriously limit the therapeutic efficacy of ROS-based strategies. Herein, we have developed an acidic biofilm microenvironment-responsive antibacterial nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The three-in-one nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in a slightly acidic environment, where Cu2+ catalyzes the conversion of H2O2 into hydroxyl radical (•OH) and consumes the highly expressed GSH to disrupt the redox homeostasis. With the assistance of an 808 nm laser, the loaded ICG not only triggers the production of singlet oxygen (1O2) by a photodynamic process, but also provides photonic hyperpyrexia that further promotes the Fenton-like reaction for enhancing •OH production and induces thermal decomposition of CuO2 for the O2-self-supplying 1O2 generation. The CuO2/ICG@CBSA with laser irradiation demonstrates photothermal-augmented multi-mode synergistic bactericidal effect and is capable of inhibiting biofilm formation and eradicating the biofilm bacteria. Further in vivo experiments suggest that the CuO2/ICG@CBSA can effectively eliminate wound infections and accelerate wound healing. The proposed three-in-one nanotherapeutics with O2/H2O2-self-supplied ROS generating capability show great potential in treating biofilm-associated bacterial infections. STATEMENT OF SIGNIFICANCE: Here, we have developed an acidic biofilm microenvironment-responsive nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in an acidic environment, where Cu2+ catalyzes the conversion of H2O2 into •OH and consumes the overexpressed GSH to improve oxidative stress. With the aid of an 808 nm laser, ICG provides photonic hyperpyrexia for enhancing •OH production, and triggers O2-self-supplying 1O2 generation. CuO2/ICG@CBSA with laser irradiation displays photothermal-augmented multi-mode antibacterial and antibiofilm effect. Further in vivo experiments prove that CuO2/ICG@CBSA effectively eliminates wound infection and promotes wound healing. The proposed three-in-one nanotherapeutics show great potential in treating biofilm-associated bacterial infections.
摘要：
活性氧（ROS）被广泛认为是对抗细菌感染，尤其是与生物膜相关的细菌感染的有效治疗剂。然而,生物膜微环境，包括缺氧，有限的H2O2和高谷胱甘肽（GSH）水平严重限制了基于ROS的策略的治疗效果。在这里，我们开发了一种酸性生物膜微环境响应型抗菌纳米平台，该平台由负载有原位合成的过氧化铜（CuO2）的铜掺杂牛血清白蛋白（CBSA）和吲哚菁绿（ICG）组成。三合一纳米治疗剂（CuO2/ICG@CBSA）能够在微酸性环境中释放Cu2和H2O2，其中Cu2+催化H2O2转化为羟基自由基(·OH)并消耗高表达的GSH以破坏氧化还原稳态。在808nm激光的辅助下，加载的ICG不仅通过光动力学过程触发单线态氧（1O2）的产生，但也提供了光子高热，进一步促进了Fenton样反应以增强•OH的产生，并诱导了CuO2的热分解，用于O2自供应1O2的产生。具有激光照射的CuO2/ICG@CBSA表现出光热增强的多模式协同杀菌作用，并且能够抑制生物膜的形成并根除生物膜细菌。进一步的体内实验表明，CuO2/ICG@CBSA可以有效消除伤口感染并加速伤口愈合。所提出的具有O2/H2O2自供ROS产生能力的三合一纳米治疗剂在治疗生物膜相关的细菌感染方面显示出巨大潜力。重要声明：这里，我们开发了一种酸性生物膜微环境响应性纳米平台，该平台由负载有原位合成的过氧化铜（CuO2）的铜掺杂牛血清白蛋白（CBSA）和吲哚菁绿（ICG）组成。纳米治疗剂（CuO2/ICG@CBSA）能够在酸性环境中释放Cu2和H2O2，其中Cu2+催化H2O2转化为·OH并消耗过表达的GSH以改善氧化应激。在808nm激光的帮助下，ICG提供光子高热以增强•OH产生，并触发O2自供应1O2的生成。激光辐照的CuO2/ICG@CBSA具有光热增强的多模抗菌和抗生物膜效果。进一步的体内实验证明CuO2/ICG@CBSA有效地消除了伤口感染并加速了伤口愈合。所提出的三合一纳米治疗剂在治疗生物膜相关的细菌感染方面显示出巨大的潜力。
