Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Department of Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
ACS Nano. 2024 Mar 5;18(9):6990-7010. doi: 10.1021/acsnano.3c10172. Epub 2024 Feb 22.
The clinical treatment efficacy for implant-associated infections (IAIs), particularly those caused by Methicillin-resistant (MRSA), remains unsatisfactory, primarily due to the formation of biofilm barriers and the resulting immunosuppressive microenvironment, leading to the chronicity and recurrence of IAIs. To address this challenge, we propose a light-induced immune enhancement strategy, synthesizing BSA@MnO@Ce6@Van (BMCV). The BMCV exhibits precise targeting and adhesion to the biofilm-infected region, coupled with its capacity to catalyze oxygen generation from HO in the hypoxic and acidic biofilm microenvironment (BME), promoting oxygen-dependent photodynamic therapy efficacy while ensuring continuous release of manganese ions. Notably, targeted BMCV can penetrate biofilms, producing ROS that degrade extracellular DNA, disrupting the biofilm structure and impairing its barrier function, making it vulnerable to infiltration and elimination by the immune system. Furthermore, light-induced reactive oxygen species (ROS) around the biofilm can lyse , triggering bacterium-like immunogenic cell death (ICD), releasing abundant immune costimulatory factors, facilitating the recognition and maturation of antigen-presenting cells (APCs), and activating adaptive immunity. Additionally, manganese ions in the BME act as immunoadjuvants, further amplifying macrophage-mediated innate and adaptive immune responses and reversing the immunologically cold BME to an immunologically hot BME. We prove that our synthesized BMCV elicits a robust adaptive immune response in vivo, effectively clearing primary IAIs and inducing long-term immune memory to prevent recurrence. Our study introduces a potent light-induced immunomodulatory nanoplatform capable of reversing the biofilm-induced immunosuppressive microenvironment and disrupting biofilm-mediated protective barriers, offering a promising immunotherapeutic strategy for addressing challenging IAIs.
植入物相关感染(IAI)的临床治疗效果,特别是耐甲氧西林金黄色葡萄球菌(MRSA)引起的感染,仍然不尽如人意,主要是因为生物膜屏障的形成和由此产生的免疫抑制微环境导致 IAI 的慢性和复发。为了应对这一挑战,我们提出了一种光诱导免疫增强策略,合成了 BSA@MnO@Ce6@Van(BMCV)。BMCV 表现出对生物膜感染区域的精确靶向和粘附能力,同时能够在缺氧和酸性生物膜微环境(BME)中催化 HO 生成氧气,促进依赖氧气的光动力治疗效果,同时确保锰离子的持续释放。值得注意的是,靶向 BMCV 可以穿透生物膜,产生 ROS 降解细胞外 DNA,破坏生物膜结构并损害其屏障功能,使其易受免疫系统的渗透和消除。此外,生物膜周围光诱导的活性氧(ROS)可以裂解,触发类似细菌的免疫原性细胞死亡(ICD),释放丰富的免疫共刺激因子,促进抗原呈递细胞(APC)的识别和成熟,并激活适应性免疫。此外,BME 中的锰离子作为免疫佐剂,进一步放大巨噬细胞介导的固有和适应性免疫反应,将免疫冷的 BME 转变为免疫热的 BME。我们证明我们合成的 BMCV 在体内引发了强烈的适应性免疫反应,有效清除原发性 IAI 并诱导长期免疫记忆以防止复发。我们的研究引入了一种强大的光诱导免疫调节纳米平台,能够逆转生物膜诱导的免疫抑制微环境并破坏生物膜介导的保护屏障,为解决具有挑战性的 IAI 提供了一种有前途的免疫治疗策略。
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