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表面纳米沉积使局部产生杀菌的超级 CAR-巨噬细胞，加速假体周围骨整合。

Surficial nano-deposition locoregionally yielding bactericidal super CAR-macrophages expedites periprosthetic osseointegration.

机构信息

NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Jinan, Shandong Province 250012, China.

Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province 250021, China.

出版信息

Sci Adv. 2023 Jun 2;9(22):eadg3365. doi: 10.1126/sciadv.adg3365. Epub 2023 May 31.

DOI:10.1126/sciadv.adg3365
PMID:37256944
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10413653/
Abstract

Tracking and eradicating in the periprosthetic microenvironment are critical for preventing periprosthetic joint infection (PJI), yet effective strategies remain elusive. Here, we report an implant nanoparticle coating that locoregionally yields bactericidal super chimeric antigen receptor macrophages (CAR-MΦs) to prevent PJI. We demonstrate that the plasmid-laden nanoparticle from the coating can introduce -targeted CAR genes and caspase-11 short hairpin RNA (CASP11 shRNA) into macrophage nuclei to generate super CAR-MΦs in mouse models. CASP11 shRNA allowed mitochondria to be recruited around phagosomes containing phagocytosed bacteria to deliver mitochondria-generated bactericidal reactive oxygen species. These super CAR-MΦs targeted and eradicated and conferred robust bactericidal immunologic activity at the bone-implant interface. Furthermore, the coating biodegradability precisely matched the bone regeneration process, achieving satisfactory osteogenesis. Overall, our work establishes a locoregional treatment strategy for priming macrophage-specific bactericidal immunity with broad application in patients suffering from multidrug-resistant bacterial infection.

摘要

在假体周围微环境中追踪和根除 是预防假体周围关节感染 (PJI) 的关键，但仍难以实现有效的策略。在这里，我们报告了一种植入物纳米粒子涂层，该涂层可局部产生杀菌性超级嵌合抗原受体巨噬细胞 (CAR-MΦ) 以预防 PJI。我们证明，涂层中的载有质粒的纳米粒子可以将 -靶向 CAR 基因和 Caspase-11 短发夹 RNA (CASP11 shRNA) 引入巨噬细胞核中，以在小鼠模型中生成超级 CAR-MΦ。CASP11 shRNA 允许线粒体被募集到含有吞噬细菌的吞噬体周围，以传递线粒体产生的杀菌活性氧物质。这些超级 CAR-MΦ 靶向并根除了 ，并在骨-植入物界面处赋予了强大的杀菌免疫活性。此外，涂层的生物降解性与骨再生过程精确匹配，实现了令人满意的成骨。总的来说，我们的工作建立了一种局部治疗策略，用于启动巨噬细胞特异性杀菌免疫，在患有多药耐药细菌感染的患者中有广泛的应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bc7/10413653/88cf04b94f34/sciadv.adg3365-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bc7/10413653/39b43c30f49a/sciadv.adg3365-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bc7/10413653/88cf04b94f34/sciadv.adg3365-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bc7/10413653/39b43c30f49a/sciadv.adg3365-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bc7/10413653/fc2c39d454cf/sciadv.adg3365-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bc7/10413653/626b7623264d/sciadv.adg3365-f3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bc7/10413653/88cf04b94f34/sciadv.adg3365-f7.jpg

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