单细胞转录组驱动的级联响应水凝胶设计，带有仿生纳米细胞起搏器，用于老年骨再生
Single-cell transcriptomic-driven design of cascade-responsive hydrogel with bioinspired nanocellular pacemaker for aged bone regeneration.
摘要(中文译文)
年龄相关性骨缺损的修复效果仍然不佳，其原因在于衰老骨髓间充质干细胞（BMSCs）与促炎巨噬细胞之间形成的恶性循环。我们通过单细胞转录组学揭示昼夜节律紊乱是这一过程的潜在驱动因素，并提出“修复内在时钟、重编程外在免疫”的策略。受能够感知信号并纠正节律的心脏起搏器启发，我们构建了具有“感知—释放—调控”范式的纳米细胞起搏器（AMC），用于衰老骨再生。AMC由负载褪黑素的钴基金属有机框架（MOF）组成，其表面包覆来源于新一代益生菌Akkermansia muciniphila的膜囊泡。钴基MOF作为一种人工传感器，能够特异性感知衰老相关信号，并在衰老微环境中释放褪黑素。褪黑素的靶向递送可修复内在时钟，并通过精确调控昼夜节律抑制p53和TNF信号通路，从而使BMSCs恢复年轻化。同时，AMC上的益生菌膜可在衰老微环境中主动将巨噬细胞重编程为促再生的M2表型。为实现微创递送，我们开发了一种具有活性氧响应性硼酸酯键的双网络水凝胶，用于AMC的时空释放。在衰老小鼠中，这一级联响应性治疗系统通过打破衰老—炎症恶性循环，在4周内完全修复骨缺损，为年龄相关性组织修复提供了一种新的“细胞起搏”范式。
Abstract
Age-related bone defects remain poorly repaired due to a vicious cycle involving senescent bone marrow mesenchymal stem cells (BMSCs) and pro-inflammatory macrophages. We unveil circadian disruption as the underlying driver via single-cell transcriptomics and propose an "internal clock-repairing, external immunity-reprogramming" strategy. Inspired by cardiac pacemakers that sense signals and rectify rhythms, we engineer nanocellular pacemakers (AMC) with a "sense-release-regulate" paradigm for aged bone regeneration. AMC comprises melatonin-loaded, cobalt-based metal-organic frameworks (MOF) coated with membrane vesicles derived from the new generation of probiotic Akkermansia muciniphila. The cobalt-based MOF functions as an artificial sensor that specifically senses senescence-associated signals to release melatonin in the senescent microenvironment. The targeted delivery of melatonin repairs the internal clock and rejuvenates BMSCs by precisely regulating circadian rhythms to inhibit p53 and TNF signaling pathways. While probiotic membrane on AMC actively reprograms macrophages toward a pro-regenerative M2 phenotype in the senescent niche. To enable minimally invasive delivery, a dual-network hydrogel with reactive oxygen species-responsive boronic ester bonds is developed for spatiotemporal release of AMC. In aged mice, this cascade-responsive therapeutic system fully repairs bone defects within 4 weeks by breaking the senescence-inflammation vicious cycle, offering a novel "cellular pacing" paradigm for age-related tissue repair.
如何引用
AMA
Hui-Yun Gu, Peng Bao, Wen-Qiang Qu, Xiao-Dong Lv, Meng Yuan, Bao-Ting Dong, et al. Single-cell transcriptomic-driven design of cascade-responsive hydrogel with bioinspired nanocellular pacemaker for aged bone regeneration.. Biomaterials. 2027; doi:10.1016/j.biomaterials.2026.124581.
APA
Hui-Yun Gu, Peng Bao, Wen-Qiang Qu, Xiao-Dong Lv, Meng Yuan, Bao-Ting Dong, et al (2027). Single-cell transcriptomic-driven design of cascade-responsive hydrogel with bioinspired nanocellular pacemaker for aged bone regeneration.. Biomaterials. https://doi.org/10.1016/j.biomaterials.2026.124581
GB/T 7714
Hui-Yun Gu, Peng Bao, Wen-Qiang Qu, Xiao-Dong Lv, Meng Yuan, Bao-Ting Dong, et al. Single-cell transcriptomic-driven design of cascade-responsive hydrogel with bioinspired nanocellular pacemaker for aged bone regeneration.[J]. Biomaterials, 2027 doi:10.1016/j.biomaterials.2026.124581.
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