Abstract:
The fracture healing outcome is largely dependent on the quantities as well as osteogenic differentiation capacities of mesenchymal stem cells (MSCs) at the lesion site. Herein, macrophage membrane (MM)-reversibly cloaked nanocomplexes (NCs) are engineered for the lesion-targeted and hierarchical co-delivery of short stromal derived factor-1α peptide (sSDF-1α) and Ckip-1 small interfering RNA (Ckip-1 siRNA, siCkip-1) to promote bone repair by concurrently fostering recruitment and osteogenic differentiation of endogenous MSCs. To construct the NCs, a membrane-penetrating α-helical polypeptide first assembles with siCkip-1, and the cationic NCs are sequentially coated with catalase and an outer shell of sSDF-1α-anchored MM. Due to MM-assisted inflammation homing, intravenously injected NCs could efficiently accumulate at the fractured femur, where catalase decomposes the local hydrogen peroxide to generate oxygen bubbles that drives the shedding of sSDF-1α-anchored MM in the extracellular compartment. The exposed, cationic inner core thus enables robust trans-membrane delivery into MSCs to induce Ckip-1 silencing. Consequently, sSDF-1α-guided MSCs recruitment cooperates with siCkip-1-mediated osteogenic differentiation to facilitate bone formation and accelerate bone fracture healing. This study provides an enlightened strategy for the hierarchical co-delivery of macromolecular drugs into different cellular compartments, and it also renders a promising modality for the management of fracture healing.
摘要:
骨折愈合结果很大程度上取决于病变部位的间充质干细胞(MSC)的数量和成骨分化能力。在这里,巨噬细胞膜(MM)可逆掩蔽的纳米复合物(NCs)被设计用于短基质衍生因子1α肽(sSDF-1α)和Ckip-1小干扰RNA(Ckip-1siRNA,siCkip-1)通过同时促进内源性MSCs的募集和成骨分化来促进骨修复。为了建立NC,穿透膜的α-螺旋多肽首先与siCkip-1组装,然后将阳离子NC依次用过氧化氢酶和sSDF-1α锚定MM的外壳包被。由于MM辅助炎症归巢,静脉注射NC可以有效地积聚在股骨骨折处,其中过氧化氢酶分解局部过氧化氢以产生氧气气泡,从而驱使sSDF-1α锚定的MM在细胞外室中脱落。暴露的,因此,阳离子内核能够实现稳健的跨膜递送到MSC中以诱导Ckip-1沉默。因此,sSDF-1α引导的MSCs募集与siCkip-1介导的成骨分化协作以促进骨形成并加速骨折愈合。本研究为大分子药物分层共递送到不同的细胞区室提供了一种开明的策略,它也为骨折愈合的管理提供了一种有希望的方式。