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Mitophagy-Replenishment Strategy Targeting the Aberrant Endogenous dsDNA to Enhance Bone Healing Quality in the Elderly

ABSTRACT: The increased incidence of delayed bone healing in elderly patients is primarily driven by the senescence of bone marrow mesenchymal stem cells (BMSCs), yet the upstream molecular triggers remain incompletely defined. This study elucidates a novel senescence-driving mechanism: impaired mitophagy and BAX oligomerization-mediated minority mitochondrial outer membrane permeabilization (miMOMP) trigger endogenous dsDNA leakage. This leakage activates the cGAS–STING signaling axis, establishing a vicious cycle that accelerates BMSC senescence and impairs osteogenesis. To precisely intervene, we developed a targeted composite delivery system (GM-UMPA) comprising AE105-functionalized hollow mesoporous polydopamine (HMPDA) nanoparticles loaded with the mitophagy inducer urolithin A (UA), encapsulated within injectable gelatin methacryloyl (GelMA) microspheres. The hollow mesoporous architecture provides a distinct structural advantage by significantly amplifying drug-loading capacity compared to conventional materials, while surface AE105 peptides enable highly specific uPAR-mediated endocytosis into senescent cells. Crucially, the weakly basic HMPDA framework exhibits pH-responsive drug release characteristics, triggering rapid intracellular UA liberation specifically within the acidic microenvironment of senescent BMSCs. Validated using an in vitro BMSC replicative senescence model and an in vivo critical-sized femoral condyle defect model in aged rats, this hierarchical platform successfully cleared damaged mitochondria, suppressed senescence-associated secretory phenotypes (SASP), and substantially accelerated high-quality bone regeneration. Ultimately, this mitophagy-replenishment strategy offers a structurally innovative, responsive nanomedicine paradigm for treating age-related bone healing disorders.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE339437 | GEO | 2026/07/28

REPOSITORIES: GEO

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Project description:Dyskeratosis congenita (DC) is an inherited multi-system disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the bone marrow stromal cell population (BMSCs, also known as bone marrow-derived mesenchymal stem cells), may contribute to the hematological phenotype. TBD-BMSCs exhibited reduced clonogenicity, reduced telomerase activity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by siTERC-RNA recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the mRNA level, and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to bone marrow failure in TBD. RNA (5 mg) isolated from N-BMSCs, siNC-BMSCs and siTERC-BMSCs 72hrs after transfection using an RNeasy Mini kit (Qiagen), was reverse transcribed and hybridized to an Affymetrix GeneChip Human Genome U133 Plus 2.0 array (LMT, NCI-Frederick). Three independent replicates for each experimental condition were carried out to control for intra-sample variation. Genes that were under/over-represented by >2-fold were analyzed using GeneSpring software. Signal intensity values were normalized using RMA (Robust Multi-array Analysis) summarization and baseline transformation to median of all samples was performed. Entities were filtered based on their signal intensity values. Hierarchical clustering was performed on filtered signal intensity (>20.0), non-averaged, fold change >2. A fold change analysis (>10-fold) was performed to generate a list of top genes under/over represented between the groups.

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Mitophagy-Replenishment Strategy Targeting the Aberrant Endogenous dsDNA to Enhance Bone Healing Quality in the Elderly

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