Notwithstanding the remarkable progress in the clinical treatment of ischemic disease, proangiogenic drugs mostly suffer from their abnormal angiogenesis and potential cancer risk, and currently, no off-the-shelf biomaterials can efficiently induce angiogenesis. Here, we reported that a semisynthetic sulfated chitosan (SCS) readily engaged anti-inflammatory macrophages and increased its secretion of endogenous vascular endothelial growth factor (VEGF) to induce angiogenesis in ischemia via a VEGF-VEGFR2 signaling pathway. The depletion of host macrophages abrogated VEGF secretion and vascularization in implants, and the inhibition of VEGF or VEGFR2 signaling also disrupted the macrophage-associated angiogenesis. In addition, in a macrophage-inhibited mouse model, SCS efficiently helped to recover the endogenous levels of VEGF and the number of CD31^hiEmcn^hi vessels in ischemia. Thus, both sulfated group and pentasaccharide sequence in SCS played an important role in directing the therapeutic angiogenesis, indicating that this highly bioactive biomaterial can be harnessed to treat ischemic disease.

The senescence microenvironment, which causes persistent inflammation and loss of intrinsic regenerative abilities, is a main obstacle to effective tissue repair in elderly individuals. In this work, we find that local H₂ supply can remodel the senescence microenvironment by anti-inflammation and anti-senescence effects in various senescent cells from skeletally mature bone. We construct a H₂-releasing scaffold which can release high-dosage H₂ (911 mL/g, up to 1 week) by electrospraying polyhydroxyalkanoate-encapsulated CaSi₂ nanoparticles onto mesoporous bioactive glass. We demonstrate efficient remodeling of the microenvironment and enhanced repair of critical-size bone defects in an aged mouse model. Mechanistically, we reveal that local H₂ release alters the microenvironment from pro-inflammation to anti-inflammation by senescent macrophages repolarization and secretome change. We also show that H₂ alleviates the progression of aging/injury-superposed senescence, facilitates the recruitment of endogenous cells and the preservation of their regeneration capability, thereby creating a pro-regenerative microenvironment able to support bone defect regeneration.

Cell therapies and regenerative medicine interventions require an adequate source of therapeutic cells. Here, we demonstrate that constructing in vivo osteo-organoids by implanting bone morphogenetic protein–2–loaded scaffolds into the internal muscle pocket near the femur of mice supports the growth and subsequent harvest of therapeutically useful cells including hematopoietic stem/progenitor cells (HSPCs), mesenchymal stem cells (MSCs), lymphocytes, and myeloid cells. Profiling of the in vivo osteo-organoid maturation process delineated three stages—fibroproliferation, osteochondral differentiation, and marrow generation—each of which entailed obvious changes in the organoid structure and cell type distribution. The MSCs harvested from the osteochondral differentiation stage mitigated carbon tetrachloride (CCl ₄ )–induced chronic liver fibrosis in mice, while HSPCs and immune cells harvested during the marrow generation stage rapidly and effectively reconstituted the impaired peripheral and solid immune organs of irradiated mice. These findings demonstrate the therapeutic potentials of in vivo osteo-organoid–derived cells in cell therapies.

Osteoarthritis (OA) is a typical degenerative disease characterized primarily by the degeneration of cartilage. However, current treatments for cartilage degeneration often lead to the formation of hypertrophic cartilage and fibrocartilage, making it challenging to achieve full‐thickness cartilage. Here, dual‐modular hydrogel microparticles (dmHMPs) are developed, which enable precise spatio‐temporal modulation and dynamic equilibrium between immune responses and cartilage regeneration. dmHMPs can modulate the inflammatory microenvironment of the joint by promoting the polarization of synovial macrophages toward an anti‐inflammatory phenotype. Consequently, as inflammation is mitigated, synovium‐derived mesenchymal stem cells recruited by dmHMPs can efficiently undergo chondrogenic differentiation to repair damaged cartilage in situ. In vivo experiments demonstrate that dmHMPs significantly suppress the expression of Indian hedgehog (Ihh) and collagen type X, thereby reducing the formation of hypertrophic cartilage and preserving the structural integrity and biological functions of articular cartilage. This therapeutic modulates the dynamic balance between inflammation and repair, providing a promising approach for full‐thickness cartilage regeneration.

Ischemic stroke followed by reperfusion urgently requires safe and efficient cytoprotective strategies, a need still unmet by current pharmacotherapies. Nanotechnology holds promise for improved drug delivery to the brain, yet the efficacy of nanomaterials crossing the blood-brain barrier (BBB) is quite limited, and long-term intracranial retention of nanomaterials may provoke neurotoxicity. Leveraging the anti-inflammatory, BBB-crossing, and biosafe properties of hydrogen (H ₂ ), we develop an inflamed vessel–targeted/anchored H ₂ –producing system by modifying ZrSi ₂ nanoparticles with a P-selectin–binding peptide (ZSNP), mimicking P-selectin/P-selectin glycoprotein ligand–mediated innate immune recruitment. Rather than relying on nanoparticle penetration into the brain parenchyma, this design enables ZSNP to anchor at the BBB vasculature, where it locally and continuously generates H ₂ via hydrolysis. The released H ₂ traverses the BBB, exerting cytoprotection through antioxidant and immunomodulatory mechanisms that coordinate multicellular recovery processes. Furthermore, ZSNP promotes microglia-mediated angiogenesis and neurogenesis, guides axonal projections along neovascular trajectories, and facilitates microglia-neuron interaction via the noncanonical Wnt/Ca ²⁺ pathway. This reconstruction of the neurovascular network supports the reintegration of functional neural circuits, leading to structural and functional recovery that surpasses the effects of edaravone. By enabling sustained H ₂ release at the BBB interface without requiring nanoparticle intracranial accumulation, this strategy represents a promising and low-burden neuroprotective approach for ischemic stroke.