Dry eye disease (DED) is a progressive ocular disorder in which chronic inflammation and oxidative stress synergistically damage ocular tissues and impair vision. While topical anti-inflammatory and artificial tears therapies are the standard treatment for DED, their long-term application is limited by adverse effects and poor patient compliance. Emerging evidence suggests that systemic redox dysregulation contributes to DED pathogenesis, highlighting the potential of oral antioxidant intervention as a disease-modifying strategy. However, the clinical translation of oral antioxidants has been constrained by poor bioavailability and rapid metabolic clearance. Herein, a coral-like resveratrol nanocomplex was fabricated with a composite natural carrier of sericin and dipotassium glycyrrhizinate through a simple pH-ultrasonic-shifting method in aqueous solution, enabling effective oral delivery of this potent polyphenolic antioxidant. This coral-like nanocomplex markedly enhanced gastrointestinal stability and systemic exposure of resveratrol, increasing oral bioavailability by approximately 6.62-fold and ocular accumulation by 2.49-fold. The nanocomplex exerted robust ocular and systemic antioxidant effects and protected against experimental DED in mice. Oral administration of this nanocomplex protected against benzalkonium chloride (BAC)-induced corneal epithelial damage, tear film dysfunction, and inflammatory responses. Mechanistically, the nanocomplex alleviated oxidative damage through ocular and systemic redox homeostasis. Rather than acting solely on the ocular surface, this orally nanomedicine may provide complementary therapeutic benefits through ocular and systemic redox regulation, while also being associated with modulation of gut microbiota and metabolic profiles. These findings support oral redox intervention as a promising complementary strategy for protecting against the DED, particularly for reducing the burden of prolonged topical treatment.
Achieving periodontal regeneration in diabetic periodontitis (DPD) is hindered by a self-perpetuating vicious cycle of excessive oxidative stress and adaptive immune dysfunction. Here, using clinical samples, multi-omics profiling, and DPD rat model, we identified an association between oxidative stress and CD4+ T cell dysregulation. This process was characterized by reactive oxygen species (ROS) accumulation and Th17/Treg imbalance, which may contribute to progressive alveolar bone loss. To modulate this pathological process, we engineered a logic-gated hydrogel-nanoparticle hybrid system for hierarchical delivery of active vitamin D (AVD). This platform features a dynamic boronic ester crosslinked network that functions as a ROS-responsive switch. Upon exposure to the oxidative microenvironment, the matrix undergoes programmed degradation to scavenge ROS, triggering the rapid release of antibody-functionalized nanoparticles. These nanoparticles selectively target CD4+ T cells and deliver AVD intracellularly, where it modulates mitochondrial homeostasis and metabolic signaling pathways, thereby restoring T-cell immune homeostasis. Following this immune reset, the system transitions into a second phase where porous copper-based metal-organic frameworks provide sustained release of AVD and osteogenic Cu2+ to support long-term bone remodeling. By integrating redox-responsive actuation, targeted immunometabolic regulation, and sustained osteoimmunomodulation, this hierarchical system provides a promising therapeutic strategy for periodontal regeneration in diabetic periodontitis.
The interface around a dental implant behaves as a dynamic ecosystem. The metal surface, the colonizing microbiota, and the host immune network continually interact rather than remaining inert neighbors. Once this equilibrium breaks, a destructive cascade can feed on itself. This challenges the older view that peri-implantitis stems only from plaque infection or from mechanical overload. We integrate evidence from the peri-implantitis microenvironment to build a framework organized around an immune–microbe–metal triad, which we use to explain how biomaterials corrode in this disease. Three pillars carry intrinsic weaknesses: the titanium passive film, the biofilm's ecological balance, and host immune tolerance. When these fail together, they set off an autocatalytic corrosion cycle. Key molecular mediators—lipopolysaccharide (LPS), intracellular metal nanoparticles, and neutrophil extracellular traps (NETs)—amplify the damage. The cycle then lowers the threshold for inflammatory cell-induced corrosion (ICIC), and tissue destruction advances toward irreversibility. Against this framework we assess current therapies and where they fall short. In their place we propose multi-targeted, ecosystem-level strategies that hit the cycle at several points, aiming to restore interfacial homeostasis. Treating peri-implantitis as a nonlinear, self-reinforcing system reframes how we understand its pathogenesis, offering a roadmap toward next-generation biomaterials and combination therapies suited to the complexity of the implant–host interface.
Orthopaedic infections are increasingly prevalent in the aging population, posing a significant clinical and economic burden. Despite progress in antimicrobial therapies, challenges such as antibiotic resistance and superbug emergence persist. Gas therapy has emerged as a promising strategy for managing orthopaedic infections. Classical gasotransmitters—including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)—exhibit antibacterial and immunomodulatory effects at controlled concentrations, though improper dosing may induce adverse effects. This review critically examines the dual mechanisms through which gasotransmitters combat infection while promoting orthopaedic regeneration. We also survey advanced delivery platforms—such as smart scaffolds, nano-reservoirs, and on-demand release systems—engineered for targeted gasotransmitter delivery to infected bone tissue. Finally, we discuss current limitations and future prospects, aiming to inspire novel biomaterial designs for targeted therapeutic delivery and to advance gas therapy as a viable option for orthopaedic infection treatment.
Intervertebral disc degeneration (IDD) arises from coupled redox imbalance, inflammation, cellular senescence, nutrient limitation, matrix loss, and mechanical failure. Biomaterials can localize therapy within the avascular disc while combining microenvironmental control with structural support. However, many studies still optimize one mechanism or one disc compartment in isolation. We organize current strategies into three interdependent layers. The first is niche reprogramming through redox control, immunomodulation, metabolic rescue, and delivery of extracellular vesicles, cells, genes, or biologics. The second is precision therapeutics through endotype- and stage-matched platform selection, image-guided delivery, and response monitoring. The third is structural reconstruction of the nucleus pulposus, annulus fibrosus, and cartilaginous endplate using compartment-specific hydrogels, fibrous scaffolds, and whole-disc constructs. We critically compare evidence strength, material parameters, animal models, manufacturability, biosafety, regulatory pathways, and clinical applicability. We also propose a dual-axis decision framework that links disease endotype and degeneration stage to treatment choice. Durable regeneration will likely require coordinated control of the pathological niche, patient selection, and compartment-specific mechanics rather than a single universal material. This framework is intended to guide biomaterial design from proof of concept toward clinically relevant restoration of disc function.
Zinc (Zn)-based implants face critical challenges in clinical orthopedic applications due to rapid corrosion, localized Zn2+-induced cytotoxicity, and inadequate osteogenic activity. Herein, we report a metal-organic framework (MOF)-mediated mineralization strategy to engineer a multifunctional conductive hydrogel coating on pure zinc substrates, integrated with polypyrrole nanoparticles (Ppy NPs). This hierarchical coating design significantly enhances interfacial adhesion and reduces the in vitro corrosion volume ratio of zinc substrates by approximately 53.23% after 14 days of immersion, effectively mitigating excessive degradation-associated ion release. The MOF- mediated mineralized layer provides controlled Zn2+/Cu2+ release and stabilizes the implant interface, while Ppy NPs establish an intrinsic electroactive microenvironment. These synergistic ionic and electrical cues promote Schwann cell functional activity, enhance neurotrophic factor secretion, and subsequently facilitate mesenchymal stem cell (MSC) osteogenic differentiation through neuro-osteogenic communication. Notably, co-culture of MSCs with Schwann cells on the Zn/H@MP coating surface results in a 257% increase in alkaline phosphatase activity and a 222% enhancement in mineralized nodule formation compared to MSC mono-culture, accompanied by significant upregulation of key osteogenic markers, demonstrating the neuro-osteogenic coupling effect. In vivo evaluation in a rat bone defect model reveals that the coated implants achieve 79.46% new bone volume fraction at 8 weeks post-implantation, with accelerated osseointegration, mature bone formation, and enhanced peri-implant innervation. By integrating corrosion regulation, bioactive ion delivery, and electroactive neuro-osteogenic modulation, this multifunctional coating provides a promising strategy for next-generation biodegradable orthopedic implants.
The therapeutic potential of oligonucleotides (oligos) is limited by insufficient delivery to extrahepatic tissues. In vitro assays often fail to accurately predict in vivo behavior, while testing each oligo candidate in animals remains inherently low throughput. Here, we conceive a barcoded oligonucleotide system (BOLT), a platform that enables high-throughput in vivo evaluations of small-molecule ligands and identifies tissue-specific oligo delivery. BOLT integrates rational design of oligo barcodes, modular conjugation chemistry, and next-generation sequencing (NGS)-based quantification, allowing simultaneous evaluation of many chemically diverse ligand-oligo conjugates within a single animal. Notably, this platform is applicable in both mice and nonhuman primates (NHPs). Using BOLT, we discovered ligands with tropism for tissues such as the brain, lung, and muscle. Collectively, these results indicate that the BOLT platform can accelerate the discovery of tissue-targeting ligands for broad oligo therapeutics.
Organoids, as three-dimensional bioactive microtissues capable of recapitulating native organ architecture and function, have become valuable models in biomedical research. However, their broad adoption is constrained by subjective morphological assessment and endpoint assays that compromise standardization and scalability. This review introduces Organoid Intelligent Morphomics (OIM), an integrative analytical framework that synergizes imaging technologies with artificial intelligence to establish a “morphology–function–mechanism” mapping. OIM enables a paradigm shift from qualitative to quantitative analysis, from static to dynamic monitoring, and from superficial observation to deep molecular inference. The applications of OIM are critically examined across three interconnected domains: (1) quality control, encompassing real-time assessment through non-invasive viability quantification and morphological evaluation, as well as predictive quality control for early differentiation outcome forecasting; (2) disease deconstruction, enabling quantitative, multiscale phenotyping of disease morphology and establishing morphology–mechanism association analyses; (3) drug development, facilitating high-throughput efficacy screening, toxicity assessment, and personalized therapeutic guidance. Furthermore, we critically analyze the current data, algorithmic, and translational challenges facing OIM, propose corresponding solutions, and provide a roadmap toward artificial intelligence virtual organoids. Ultimately, OIM holds promise for establishing the critical technological infrastructure for the scalable manufacturing and clinical translation of organoid-based therapeutics.
Transdermal drug delivery is an appealing approach because it is easy to administer, bypasses first-pass metabolism, and utilizes an extensive surface area of the skin. Microneedles, as an emerging transdermal drug delivery system, offer minimal invasiveness, painlessness, and targeted in-situ treatment. However, the existing microneedle technologies rely on passive diffusion, which can result in unpredictable drug penetration profiles. To enhance the active deep penetration and diffusion of cargoes of the microneedles, gas-propelled microneedles have gradually gained attention from researchers. Gas components can improve transdermal drug delivery efficiency by enhancing drug penetration via pressure effects and bubble generation. Meanwhile, therapeutic gases themselves may function as bioactive components, providing synergistic therapeutic benefits in addition to drug delivery. Hence, Gas-propelled microneedles are promising drug delivery platforms. This review first introduces the structure of the skin and the mechanisms underlying transdermal permeation, followed by a comprehensive overview of recent advances in gas-propelled microneedles for enhancing transdermal drug delivery. We outlined the optimal application strategies based on the distinct properties of different gas-propelled microneedles. It also underscored optimal design strategies for gas-propelled microneedles, assisting formulators in making well-informed decisions. Ultimately, we discussed the current shortcomings of gas-propelled microneedles and future development directions.
Alpha-fetoprotein (AFP) plays multiple roles in hepatocellular carcinoma (HCC), driving tumor progression and immune evasion. However, clinical measurement of serum AFP levels often fails to reflect intratumoral AFP expression, especially for early-stage or well-differentiated HCC. Current imaging modalities lack the sensitivity and specificity to visualize AFP spatially within tumors. Herein, an AND-gated afterglow probe is engineered to be sequentially activated by two features of HCC microenvironment: acidic pH and elevated AFP. The probe consists of afterglow nanoparticles (PZ-NPs) functionalized with BHQ3-modified dual-aptamer DNA. Initially quenched via afterglow resonance energy transfer (ARET), the probe is activated sequentially through pH-induced triplex folding and AFP binding, which cause conformational tightening and disrupt ARET to restore afterglow luminescence. Such an activation requires an AND logic of three inputs (i.e. light, H+ and AFP), which enables a limit of detection for AFP as low as 0.31nM and ensures high specificity with negligible response to interferents. In orthotopic HCC, the probe achieved an 8.3-fold tumor-to-liver ratio (vs. 1.4-fold for fluorescence) with signals that are colocalized with luciferase-defined tumors and able to detect curcumin-mediated AFP suppression in good consistency with immunohistochemistry results. Ex vivo imaging of resected livers further confirmed tumor-specific activation, supporting AFP-selective in vivo imaging and microenvironment-gated biomarker detection in HCC.
Gut microbiota dysbiosis is a critical factor in numerous diseases, yet current fecal microbiota (FM) transplantation therapies suffer from poor retention and inconsistent engraftment due to harsh gastric conditions or rapid clearance by bowel peristalsis. Herein, we report a thioester pre-crosslinked, low-viscosity injectable sol (Alg-NHS@αLA) formulated by directly mixing α-lipoic acid (αLA) and N-hydroxysuccinimide ester-modified sodium alginate (Alg-NHS) in a biocompatible polyethylene glycol solvent. This formulation remains flowable for minimally invasive transanal administration. Critically, upon contact with the wet colonic mucosa, tissue-derived water triggers a rapid ring-opening polymerization of αLA, inducing an in situ sol-gel transition to form a robust hydrogel network. Simultaneously, abundant carboxyl groups and unreacted NHS esters establish strong hydrogen bonds and covalent linkages with the mucosal surface, enabling robust and durable wet adhesion that conventional injectables fail to achieve. More importantly, this hydrogel harnesses continuous mucus secretion to facilitate conformal coating, achieving exceptional long-term retention exceeding 72 h while preserving the viability of the incorporated microbiota. The translational potential of this platform is validated through successful endoscopic delivery in a porcine model. By integrating rapid water-triggered gelation with robust mucosal adhesion, our Alg-NHS@αLA/FM system significantly enhances FM transplantation efficacy in a mouse colitis model, offering a promising strategy for colonic microbiome-based therapeutics.
Osteoarthritis (OA) is characterized by progressive glycosaminoglycan (GAG) depletion caused by insufficient matrix replenishment and excessive proteoglycan catabolism. Here, we developed a spatially coordinated strategy that integrates GAG deposition in the cartilage extracellular matrix (ECM) with intracellular regulation of GAG enrichment and degradation in chondrocytes. To achieve this strategy, we engineered a hierarchical “Nanorocket” comprising a chondroitin sulfate (CS)-cationic peptide Booster and an HDMBr/siADAMTS5 Satellite. The Nanorocket facilitated cartilage penetration and prolonged the intra-articular retention of both components. The Booster supported CS deposition within the cartilage extracellular matrix, whereas the internalized Satellite increased CHPF/CHSY2 expression and silenced ADAMTS5, thereby promoting GAG enrichment while limiting proteoglycan degradation. This coordinated regulation preserved GAG content, reduced matrix porosity, and maintained the mechanical properties of human cartilage explants. In a surgical OA mouse model, periodic treatment preserved cartilage thickness and matrix integrity, mitigated subchondral bone alterations, and improved gait performance. These findings establish the proof-of-concept feasibility of spatially coordinating GAG deposition and metabolism to preserve cartilage homeostasis during early OA progression.
Regenerative peripheral nerve interfaces (RPNIs) are emerging platforms capable to translate neural activity into controllable myoelectric signals. However, current clinical RPNIs rely on muscle autografts, limiting their scalability and extensive adoption. Here, we report a bioactive, ultrasound-responsive piezoelectric muscle biomaterial designed as a fully tissue-engineered alternative to autologous grafts. The construct consists of fibrinogen-based muscle tissues enriched with barium titanate nanoparticles (BTNPs, diameter∼60 nm) and supported by a biodegradable surgical membrane that promotes the formation of aligned, multinucleated myotubes. The incorporation of BTNPs imparts intrinsic piezoelectric activity to the construct, and the nanoparticles are taken up by developing myotubes, enabling remote mechanoelectrical tissue stimulation under low-intensity pulsed ultrasound (LIPUS).In vivo, piezoelectric constructs implanted around the rat peroneal nerve for two months undergo LIPUS-driven activation of internalized BTNPs, which enhances muscle maturation, and electromechanical responsiveness, yielding myoelectrical signals up to 3.2 mV upon nerve activation. Histological analyses confirm improved structural organization, increased desmin expression, and evidence of neovascularization and axonal regeneration within the engineered interface. These findings suggest that the piezoelectric constructs form stable, functional biointerfaces with peripheral nerves, and that LIPUS-driven activation of embedded BTNPs provides a non-invasive strategy to potentiate muscle development and signal transduction.This study positions LIPUS-responsive, engineered piezoelectric muscle constructs as a donor-free, bioactive platform alternative to traditional autografts for next-generation human-machine interfaces and regenerative bioelectronics.
Biomolecular coacervation is increasingly recognized as a phase-evolution process, including liquid-liquid phase separation (LLPS), resulting in metastable liquid-like states, and phase transitions that give rise to gel-like states or solid-like states. These coacervate phase states exhibit distinct structural, dynamic and mechanical characteristics, making biomolecular coacervation regulation a powerful design strategy to engineer biomaterials for a broad range of biomedical applications. In this review, we first summarize the classification of LLPS and the typical molecular driving forces. We then discuss the phase evolution of coacervates, with particular emphasis on LLPS, liquid-to-gel and liquid-to-solid transitions, the characteristics of liquid-like, gel-like and solid-like states, and the intrinsic molecular and environmental factors that regulate these processes. Finally, we examine how distinct phase-state properties govern the biomedical functions of coacervation-mediated materials, with representative applications in drug delivery, bioreactors, bioinspired adhesion and tissue engineering scaffolds. Hopefully, this review could provide a unified framework for understanding coacervation-mediated materials as programmable biomolecular coacervate systems and for guiding their rational design in biomedical applications.
The immunosuppressive tumor microenvironment limits the efficacy of therapies that target metabolism. Here we show a strategy of dual metabolic regulation that simultaneously reprogramming glycolysis in cancer cells and fructose metabolism in tumor-associated macrophages, transforms the metabolic ecosystem from pro-tumor to antitumor, eliciting systemic immunity. Through pan-cancer single-cell analysis, we identified a metabolic division of labor: cancer cells exhibit hyperactive glycolysis, while immunosuppressive macrophages display elevated fructose metabolism. We uncovered that manganese ions (Mn2+) selectively suggest a potential inhibitory effect on glycolysis, induce pyroptosis, yet paradoxically upregulate fructose metabolism in M2-like macrophages, creating an exploitable vulnerability. To harness this dual activity, we engineered a 3D-printed nanoporous Cu-Mn alloy (CuMn) that provides sustained intratumoral release of Mn2+ and delivers a fructokinase inhibitor. In a bilateral breast carcinoma model, a single intratumoral implantation of this platform suppressed primary tumor growth and eradicated distant untreated lesions. Therapeutic efficacy was associated with macrophage reprogramming, which remodeled the immune microenvironment, alleviated T cell exhaustion, and inhibited distant tumor growth, suggesting potential systemic antitumor effects. Local delivery of the nano platform offers a strategy to overcome tumor immunosuppression and enhance cancer immunotherapy.
Hepatic osteodystrophy (HOD) is a debilitating metabolic bone disorder inextricably linked to chronic liver disease, with its prevalence surging alongside the global rise of metabolic dysfunction-associated steatohepatitis (MASH). Current clinical interventions remain fragmented, failing to concurrently address the upstream hepatic lipotoxicity and the downstream skeletal deterioration. Herein, we engineer copper-doped bioactive glasses (CuBGs) as a multifunctional ion-therapy nanoplatform that exploits natural hepatic tropism to synchronously rescue MASH-HOD pathology via targeted reprogramming of the liver-bone axis. By delivering localized therapeutic ions, CuBGs orchestrate robust hepatic metabolic recovery: they enhance glucose tolerance and restore mitochondrial oxidative phosphorylation (OXPHOS), thereby effectively halting intrahepatic triglyceride accumulation and quenching ROS-driven inflammation. Crucially, this hepatic rescue reactivates the liver-bone endocrine crosstalk by robustly upregulating the secretion of the hepatokine lecithin-cholesterol acyltransferase (LCAT). Systemic LCAT restoration directly stimulates profound osteoblastogenesis and new bone formation, decisively reversing MASH-induced trabecular bone loss without acting as a conventional anti-resorptive agent. This dual-organ modulation comprehensively ameliorates the interconnected multi-organ microenvironment in MASH-HOD without inducing systemic toxicity. Ultimately, this bioactive glass-mediated copper delivery system establishes a novel, highly scalable strategy for ion-based nanotherapeutics, offering a promising and integrated strategy for complex liver-bone comorbidities.
Electrical stimulation (EStim) has been used to exercise denervated muscle pending nerve regeneration, to prevent muscle atrophy. However, higher EStim intensity is required to achieve maximal therapeutic efficacy, which is challenging because conventional electrodes generate heat and alter pH, potentially causing tissue damage. Here, we developed and utilized a novel hydrogel ionic circuit (HIC)-based EStim system that is ionically conductive and prevents tissue damage. This HIC was safely used to deliver a high EStim intensity of 32 mA both in vitro and in vivo without substantial cell death or tissue damage. The high EStim intensity promoted the differentiation of myoblasts into myotubes, increased growth factor production, and enhanced the release of extracellular vesicles. In a long-gap sciatic nerve rat model, high-intensity EStim reduced muscle atrophy, stabilized the neuromuscular junction, and upregulated regenerative proteins, while also promoting nerve regeneration. Conclusively, these findings demonstrate that the HIC provides a safe and effective platform for high-intensity EStim to enhance neuromuscular regeneration and functional recovery.
RNA therapeutics provide a revolutionary means of treating a variety of diseases by precisely regulating gene expression and protein synthesis, with great medical significance. However, there are three key challenges to its clinical application: the inherent instability of RNA, the need for controlled regulation of RNA function, and the lack of an efficient delivery system. Computational strategies provide complementary tools for analyzing and optimizing RNA sequence, structure, function, and delivery, accelerating the rational design of RNAs and the optimization of delivery systems. This review systematically introduces two core advances in the field of RNA therapy: (1) the design and optimization of RNAs based on predictive modeling and algorithmic screening; (2) the intelligent transformation of the delivery system through data-driven methods. Based on these developments, we discuss three future directions for computational RNA molecular design across the dimensions of design algorithms, design mechanisms, and design architectures. This review not only summarizes computational approaches developed to address key challenges in RNA therapeutics, but also highlights opportunities for integrated RNA-delivery co-design. These advances may provide useful insights for the development of next-generation precision therapeutics and their future clinical translation.
The impaired regenerative capacity of osteoporotic individuals poses a significant challenge to the repair of bone defects. In the osteoporotic microenvironment, low pH, excessive reactive oxygen species (ROS), and chronic inflammation create a self-perpetuating vicious cycle that impedes healing. However, conventional therapies fail to sustainably improve the damaged microenvironment. Here, a pH/ROS dual responsive nanocomposite hydrogel (Z-QCDs@M2-Migs@OHA-PP) was developed based on oxidized hyaluronic acid (OHA), phenylboronic acid-grafted ε-polylysine (PP), quercetin-derived carbon dots (QCDs) loaded ZIF-8 (Z-QCDs) and M2 macrophage-derived migrasomes (M2-Migs), which possesses intrinsic antioxidant and osteogenic differentiation-promoting capabilities. Due to the presence of dynamic. Schiff base bonds and boronate bonds, the hydrogel exhibited injectability and pH/ROS dual responsiveness. OHA-PP releases Z-QCDs and M2-Migs on demand in response to changes in pH and ROS levels. Z-QCDs exhibit strong antioxidant and nanozyme activity, capable of scavenging ROS, suppressing inflammatory responses, and promoting M2 macrophage polarization. Furthermore, the introduction of M2-Migs as an osteogenic activator further enhances the capacity for osteogenic differentiation. Transcriptomic and Western blot analyses revealed that the hydrogel promotes osteogenic differentiation by activating the PI3K-AKT signaling pathway. In a mouse osteoporotic bone defect model, the nanocomposite hydrogel effectively inhibited ferroptosis, modulated inflammation, and promoted new bone formation. Therefore, this hydrogel system, which combines therapeutic rationale with microenvironmental regulation, offers a promising strategy for the regeneration of osteoporotic bone defects.
The regeneration of osteoporotic bone fractures remains a significant clinical challenge, primarily due to the iron overload-induced functional impairment in osteoporosis-angiogenesis coupling. Here, we developed a transmetallic biomimetic hydrogel implant (TBH) to address this issue. The TBH was fabricated by crosslinking CP1-modified hyaluronic acid (HA) with catechol-modified chitosan (CS-CT), of which the catechol groups enabled efficient loading of pro-osteogenic Co2+ ions. Upon implantation into osteoporotic bone fracture sites, the transmetallic activity of the hydrogel allows excess Fe3+ ions to competitively replace the pre-incorporated Co2+ ions, driven by the stronger affinity of Fe3+ for catechol groups, effectively sequestering the free iron species to alleviate osteoporosis-associated iron overload while enabling the controlled release of Co2+ locally. Notably, the TBH-enabled iron sequestering substantially mitigates iron overload and restores mitochondrial function in both endothelial cells (ECs) and bone marrow mesenchymal stem cells (MSCs), while the synchronously released Co2+ activates EC metabolism and promotes HIF-1α-driven type H vessel formation as well as driving osteogenic differentiation of MSCs through paracrine signaling. Fe3+-catechol coordination also significantly enhances the mechanical properties of the hydrogel network and optimizes its degradation profiles to match local osteogenesis. In addition, TBH gradually releases osteogenic bovine bone collagen peptides to promote mineralization through spontaneous degradation. These merits cooperatively improve bone regeneration in osteoporotic rat models, providing an approach for osteoporotic bone fracture healing in the clinic.
