BiomaterialsAug 28, 2026

Designing a smart hydrogel with tiny cell-like pacemakers to help heal aged bones, guided by single-cell gene analysis

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 29, 2026

Abstract

In aged mice, a cascade-responsive therapeutic system fully repairs bone defects within 4 weeks.

Age-related bone defects are linked to a cycle involving senescent bone marrow stem cells and pro-inflammatory macrophages.
Circadian disruption is identified as a key factor driving this cycle.
Engineered nanocellular pacemakers release melatonin in response to senescence-associated signals.
Melatonin delivery is associated with the rejuvenation of bone marrow stem cells by regulating circadian rhythms and inhibiting specific signaling pathways.
Probiotic membrane components on the nanocellular pacemakers may reprogram macrophages towards a pro-regenerative phenotype.
A dual-network hydrogel facilitates the targeted and timed release of the therapeutic system.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Designing a smart hydrogel with tiny cell-like pacemakers to help heal aged bones, guided by single-cell gene analysis

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief