2. Academic Validation
  3. siAkt2-Loaded Nanoparticles Reprogramming Macrophages to M2 Phenotype for Effective Bone Defect Repair

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

  • Adv Mater. 2025 Nov 4:e10507. doi: 10.1002/adma.202410507.
Shengjie Cui 1,  Xiaowei Wu 2,  Xiaotong Yu 2,  Yiqian Huang 3,  Daixing Zhang 3,  Haotian Chen 2,  Boon Chin Heng 4,  Qing Cai 3,  Yixiang Wang 5,  Yan Gu 2,  Xuliang Deng 6
Affiliations

Affiliations

  • 1 Department of Orthodontics, Department of General Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, 100081, P. R. China.
  • 2 Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China.
  • 3 State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.
  • 4 Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China.
  • 5 Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China.
  • 6 Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical DevicesNMPA Key Laboratory for Dental Materials & Beijing Key Laboratory of Biomaterials for Oral Disease & Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China.
PMID: 41189396 DOI: 10.1002/adma.202410507
Abstract

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 enhancing tissue regeneration.

Keywords

Akt2; RNA delivery; macrophage polarization; metabolic reprogramming; nanoparticles.

Figures
Products