Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, PR China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, PR China.
J Control Release. 2023 Jan;353:591-610. doi: 10.1016/j.jconrel.2022.12.014. Epub 2022 Dec 12.
Intracellular Methicillin-Resistant Staphylococcus aureus (MRSA) remains a major factor of refractory and recurrent infections, which cannot be well addressed by antibiotic therapy. Here, we design a cellular infectious microenvironment-activatable polymeric nano-system to mediate targeted intracellular drug delivery for macrophage reprogramming and intracellular MRSA eradication. The polymeric nano-system is composed of a ferrocene-decorated polymeric nanovesicle formulated from poly(ferrocenemethyl methacrylate)-block-poly(2-methacryloyloxyethyl phosphorylcholine) (PFMMA-b-PMPC) copolymer with co-encapsulation of clofazimine (CFZ) and interferon-γ (IFN-γ). The cellular-targeting PMPC motifs render specific internalization by macrophages and allow efficient intracellular accumulation. Following the internalization, the ferrocene-derived polymer backbone sequentially undergoes hydrophobic-to-hydrophilic transition, charge reversal and Fe release in response to intracellular hydrogen peroxide over-produced upon infection, eventually triggering endosomal escape and on-site cytosolic drug delivery. The released IFN-γ reverses the immunosuppressive status of infected macrophages by reprogramming anti-inflammatory M2 to pro-inflammatory M1 phenotype. Meanwhile, intracellular Fe-mediated Fenton reaction together with antibiotic CFZ contributes to increased intracellular hydroxyl radical (•OH) generation. Ultimately, the nano-system achieves robust potency in ablating intracellular MRSA and antibiotic-tolerant persisters by synchronous immune modulation and efficient •OH killing, providing an innovative train of thought for intracellular MRSA control.
细胞内耐甲氧西林金黄色葡萄球菌（MRSA）仍然是难治性和复发性感染的主要因素，抗生素治疗对此难以有效解决。在这里，我们设计了一种细胞感染微环境激活型聚合物纳米系统，用于介导靶向细胞内药物递送来重编程巨噬细胞并消除细胞内 MRSA。该聚合物纳米系统由一个二茂铁修饰的聚合物纳米囊泡组成，该囊泡由聚（二茂铁甲基甲基丙烯酸酯）-嵌段-聚（2-甲基丙烯酰氧乙基磷酸胆碱）（PFMMA-b-PMPC）共聚物构成，共包载氯法齐明（CFZ）和干扰素-γ（IFN-γ）。细胞靶向的 PMPC 基序使巨噬细胞能够特异性内化，并允许有效进行细胞内积累。在内化后，二茂铁衍生的聚合物主链依次经历疏水性到亲水性的转变、电荷反转和 Fe 释放，以响应感染时细胞内过产生的过氧化氢，最终触发内体逃逸和现场细胞质药物递送。释放的 IFN-γ 通过重编程抗炎 M2 为促炎 M1 表型来逆转感染巨噬细胞的免疫抑制状态。同时，细胞内 Fe 介导的芬顿反应与抗生素 CFZ 一起有助于增加细胞内羟基自由基（•OH）的产生。最终，该纳米系统通过同步免疫调节和高效的•OH 杀伤，在消灭细胞内 MRSA 和抗生素耐受持久菌方面具有强大的功效，为细胞内 MRSA 控制提供了创新思路。
