siAkt2‐Loaded Nanoparticles Reprogramming Macrophages to M2 Phenotype for Effective Bone Defect Repair

作者：Shengjie Cui, Xiaowei Wu, Xiaotong Yu, Yiqian Huang, Daixing Zhang, Haotian Chen, Boon Chin Heng, Qing Cai, Yixiang Wang, Yan Gu, Xuliang Deng · 发表于：Advanced Materials · 年份：2025 · DOI：10.1002/adma.202410507 · 被引用次数：4 · 研究领域：RNA Interference and Gene Delivery、Immune cells in cancer、Graphene and Nanomaterials Applications

Targeted siRNA delivery has been widely used to regulate cell function. However, the rapid degradation of siRNA within macrophages upon delivery severely limits its utility for regulating macrophage function. Here, a novel technique is developed to compact large amounts of siAkt2 strands into delivery nanoparticles, to achieve massive and sustained intracellular release of siAkt2 that overwhelms the degradation capacity of macrophages. Microspheres of RNA complexes are prepared by rolling circle transcription. For better deliverability, siAkt2 microspheres are compacted by cholesterol-modified DNA, and encapsulated by Poly-(L-lactic acid) (PLLA). These PLLA-encapsulated siAkt2-compacted nanoparticles (siAkt2 RNP@PLLA NPs), each containing multiple repeated siAkt2 sequences, displayed long-term stability and maintenance of integrity within body fluids and acidic environments. Extensive endocytosis by RAW 264.7 is followed by continuous massive siAkt2 release into the cytosol, which significantly increased Akt2 gene silencing, metabolic reprogramming, as well as enhanced macrophage alternative polarization to the pro-regenerative M2 phenotype. Local administration of siAkt2 RNP@PLLA NPs in bone defects caused by periodontitis markedly induced macrophage alternative M2 polarization and enhanced bone regeneration. Therefore, the study provides a novel and highly efficient siRNA delivery system for regulating macrophage function, which can be a promising therapeutic strategy for e...