Abstract Long-circulating polyethylene glycol bottlebrush polymers (BrushPEG) are attractive drug carriers, but their nondegradable backbones cause persistent tissue retention, raising concerns about long-term safety and clinical translation. Here, we report a hydrolytically degradable PEG bottlebrush polymer (D-BrushPEG) created by incorporating 7-oxa-2,3-diazanorbornene (ODAN) units into the backbone. D-BrushPEG retains prolonged circulation (elimination half-life ≈24.7 h, compared with ≈0.78 h for a small-molecule dye) while undergoing controlled hydrolysis that greatly improves systemic and tissue clearance. More than 99% of the circulating signal is removed within 13 days, accompanied by a near-complete loss of liver and skin fluorescence. In contrast, a nondegradable BrushPEG analog exhibits slower plasma elimination (∼5% remaining at day 13) and persistent accumulation in the liver and skin for over one month. When conjugated with gemcitabine (GEM) through a reduction-responsive self-immolative linker, D-BrushPEG demonstrated comparable antitumor efficacy to the nondegradable BrushPEG-GEM formulation. Systemic evaluation indicates comparable hepatic and renal safety profiles for both polymers, with only mild renal changes observed, while skin irritation is reduced for D-BrushPEG relative to BrushPEG. These results demonstrate that controlled backbone hydrolysis allows PEG bottlebrush polymers to balance long circulation with efficient clearance, reducing tissue persistence and the risk of side effects.

Myocardial patches, particularly collagen-based systems, have emerged as promising therapeutic platforms for repairing injured cardiac tissue after myocardial infarction (MI). However, their clinical translation remains constrained by insufficient wet-tissue adhesion, mechanical mismatch with the native myocardium, and limited regenerative bioactivity. Inspired by the interpenetrating rigid-flexible architecture of deep-sea glass sponge spicules, we developed a biomimetic hydrogel cardiac patch (PCH@D) designed to address these challenges in an integrated manner. The patch is constructed as a multi-component interpenetrating network, in which diatom-derived biosilica serves as a rigid skeletal framework and silicate ion reservoir, while a dual-network matrix of acrylated collagen and poly(acrylic acid), reinforced by catechol-functionalized hyperbranched polymers, forms a flexible organic phase that mediates wet-tissue adhesion through cooperative hydrophobic-catechol interactions by actively displacing interfacial water and forming stable covalent bonds with tissues. As a result, the PCH@D patch achieves rapid and robust adhesion to wet myocardium (40.59 ± 3.30 kPa), exhibits mechanical properties well matched to native myocardium, and offers sustained silicate ion release over 28 days. In a murine MI model, implantation of the PCH@D patch reduced cardiomyocyte apoptosis, promoted M2 macrophage polarization, enhanced angiogenesis, and effectively mitigated adverse ventricular remodeling, leading to improved cardiac function. This work highlights a bioinspired materials design strategy for cardiac patches that integrates mechanical compatibility with active biological regulation.

Conventional bone repair materials, such as β-tricalcium phosphate (β-TCP) scaffolds, are widely used in orthopedic applications due to their excellent biocompatibility and osteoconductivity. However, their regenerative efficacy is markedly compromised under diabetic microenvironments, as they lack the ability to counteract persistent oxidative stress and hyperglycemia-induced impairment of osteogenic activity. To address this limitation, we developed a strontium-baicalein (SrB) coated β-TCP scaffold (β-TCP@SrB) with integrated antioxidative and osteoinductive functions. In this system, baicalein provides robust cytoprotective and reactive oxygen species (ROS) scavenging effects under high-glucose (HG) conditions. Meanwhile, its polyphenolic structure enables strong interfacial adhesion to β-TCP and coordination-driven assembly with Sr2+ ions, which serve as potent osteogenic cues. In vitro studies demonstrated that β-TCP@SrB scaffolds effectively reduced excessive ROS accumulation and significantly enhanced osteogenic differentiation of HG-injured bone marrow mesenchymal stem cells, accompanied by activation of the Wnt signaling pathway. Furthermore, in a type 2 diabetic rat calvarial defect model, β-TCP@SrB scaffolds markedly promoted new bone formation compared with unmodified β-TCP scaffolds. Collectively, these results demonstrate a rational and clinically relevant surface-engineering strategy that integrates antioxidation and osteogenesis within a single bioactive interface, providing a promising approach for restoring bone regeneration in diabetes and potentially other metabolically compromised conditions.

Bone regeneration under diabetic conditions remains a formidable challenge, predominantly due to persistent oxidative stress, chronic inflammation, and impaired osteogenic potential of stem cells. Nanozymes have been widely employed to modulate oxidative stress and inflammation, and are considered promising candidates for diabetic bone regeneration. However, they have a limited osteogenic capacity, which substantially hinders their direct application in bone repair. Here, a series of osteogenic ion-doped Prussian blue (PB) nanozymes was designed to endow classical antioxidant PB with osteoinductive capacity, among which copper-doped PB (CuPB) exhibits optimal performance. The screened CuPB nanozyme effectively scavenges various types of excessive reactive oxygen species, suppresses inflammation, and simultaneously promotes osteogenic differentiation via activation of the phosphoinositide 3-kinase/protein kinase B (PI3K-Akt) pathway. In type II diabetic rats, both the CuPB nanoparticulate formulation and the CuPB-functionalized three-dimensional scaffold pronouncedly enhance bone regeneration in models of periodontitis-associated alveolar bone loss and cranial defects, respectively. This study establishes an integrated "osteogenic nanozyme" platform that synergistically couples antioxidant and osteoinductive functions.

Cancer is a complex disease characterized by systemic dysfunction, necessitating a balance between therapeutic efficacy and safety. Immunotherapy is a core treatment approach for activating the antitumor immune response in the human body. The development of intelligent hydrogels has provided an innovative platform for tumor immunotherapy, owing to their adjustable properties for controlled drug delivery and immune modulation. Tumor immunotherapy has achieved remarkable success in recent years. However, it continues to face critical challenges such as targeting and delivery barriers, suppression by the TME, and immune evasion and drug resistance. In response, as injectable or implantable biomaterials, hydrogels are emerging as a promising platform to address these limitations by enabling localized, controllable drug delivery and immunomodulation. This review systematically categorizes contemporary hydrogel construction strategies tailored for immunotherapy, highlighting the distinct advantages of specific architectures in diverse clinical contexts. By classifying hydrogel applications according to immune-based strategies, the work underscores their multifunctional utility as precision delivery platforms and modulators of the immune microenvironment. This comprehensive overview elucidates the progress and design principles of hydrogel-based immunotherapeutic platforms, providing valuable insights to guide future research and development in this evolving field.

Effective therapy for ischemic diseases requires not only timely restoration of perfusion but also protection of ischemic tissues from secondary insults, particularly oxidative-stress-induced injury. Here, we propose the concept of “proangiogenic nanozymes” and develop an efficient screening platform by doping angiogenic elements (Mg, Co, Cu, Zn, Sr, or Eu) into an archetypal antioxidative nanozyme, Prussian blue. Systematic assessment of catalytic activity and proangiogenic performance identified Cu-doped Prussian blue (CuPB) as the lead candidate. In addition to efficiently decomposing multiple reactive oxygen species, thereby attenuating oxidative stress, reducing apoptosis, and protecting ischemic tissues from secondary injury, CuPB nanozymes also stimulated angiogenesis, thereby accelerating tissue repair. In murine models of hind limb ischemia and myocardial infarction, CuPB conferred therapeutic benefits after both local and systemic administration, underscoring its translational potential. This proangiogenic nanozyme strategy offers an integrated and effective approach to ischemic tissue regeneration, bridging catalytic nanomedicine and vascular repair.

Introduction and Objective: Diabetic pressure ulcers are hard-to-heal chronic wounds characterized by sustained mechanical stress and local hypoxia. Here we report a pressure-sensitive, oxygengenerating bilayer hydrogel (APAD) dressing, which can accelerates wound closure, enhances neovascularization and collagen remodeling, and activates cell cycle and Wnt signaling pathways. This integrated platform offers a clinically relevant strategy for real-time monitoring and effective treatment of diabetic pressure injuries. Methods: We designed, fabricated, and systematically evaluated the APAD hydrogel in terms of structural optimization, mechanical performance, electromechanical sensitivity, and oxygenrelease behavior. Furthermore, we assessed its biocompatibility and pro-healing efficacy both in vitro and in vivo using diabetic mouse and miniature pig models, and explored the underlying molecular mechanisms through transcriptomic analyses. Results: The APAD hydrogel is structurally reinforced by the silica exoskeletons of diatoms. Meanwhile, the embedded diatoms maintain robust metabolic activity under low-light and moist wound conditions, producing oxygen in a controllable and cyclic manner that counteracts local hypoxia. Transcriptomic profiling and immunohistochemistry of APAD-treated tissue revealed upregulation of epidermal development and cell cycle pathways, along with suppression of muscle contraction-related signatures, indicating a shift toward regenerative rather than fibrotic wound remodeling, supporting the notion that oxygen microenvironment modulation directly orchestrates cellular regenerative responses at the wound site. Conclusion: The diatom-integrated APAD hydrogel offers a biologically intelligent strategy for addressing the dual pathological barriers of pressure overload and hypoxia in diabetic pressure ulcers. This system enables real-time feedback and actively promotes tissue regeneration. Disclosure H. Zhu: None. C. Yang: None. S. Wu: None. Q. Jin: None. R. Sun: None. X. Yao: None.

Polyethylene glycol (PEG) can stabilize nanoparticles and facilitate transport across biological barriers, yet the same PEG layer suppresses cellular uptake─a trade-off known as the PEG dilemma. Current strategies seek to overcome this limitation by enabling PEG shedding in response to pathological biochemical cues, but their dependence on heterogeneous microenvironments limits predictability and cross-route applicability. Here, we report a thermoresponsive PEG shedding strategy based on PEG-lipid conjugates with oxanorbornadiene linkers that cleave at physiological temperature. By varying the linker structure, PEG shedding kinetics can be modulated over pharmacologically relevant time scales, enabling mRNA-lipid nanoparticles to undergo surface transitions from sterically shielded to cell-interactive states. In inhaled delivery, rapid PEG shedding after mucus traversal restored cellular uptake and markedly enhanced pulmonary mRNA expression, resulting in inhibition of pulmonary metastases. In systemic administration, intermediate PEG shedding preserved the circulation benefit of dense PEGylation while enabling subsequent intracellular delivery, leading to improved tumor expression and antitumor efficacy. These results establish kinetic programming of PEG shedding as a design principle for dynamically regulating nanoparticle biointerfaces across distinct delivery routes.

The global prevalence of osteoporosis is rising, particularly among the elderly and post-menopausal population. Although natural flavonoids can inhibit osteoclast overactivation, their low abundance and extraction challenges limit clinical translation. In this study, we synthesized a flavonoid derivative, SZQ-4, and evaluated its therapeutic potential for post-menopausal osteoporosis (PMO). Using an RANKL-induced osteoclastogenesis model in vitro, we demonstrated through TRAP staining, RT-qPCR, and bone resorption assays that SZQ-4 significantly suppresses osteoclast formation and activity. Mechanistically, RNA-seq, Western blot, siRNA knockdown, and plasmid-based overexpression experiments revealed that SZQ-4 reduces RANKL-induced reactive oxygen species (ROS) production, regulates SIRT3 expression, and improves mitochondrial function, thereby attenuating osteoclast differentiation. In an ovariectomy-induced bone loss mouse model, SZQ-4 treatment markedly alleviated femoral bone loss, decreased osteoclast numbers, and lowered ROS levels in the bone marrow microenvironment. Collectively, our findings indicate that SZQ-4 inhibits osteoclast-driven bone resorption by modulating the ROS-SIRT3-mitochondrial function axis, highlighting its potential as a candidate for preventing pathological bone loss.

Flexure hinges are high-precision rotational joints that have long been a research focus in spatial compliant mechanisms. The type of notch profiles affects the performance of the hinge. This paper proposes a bio-inspired flexure hinge inspired by avian eggs. Based on the morphology of avian eggs, an oval curve is obtained by modifying elliptic curves to enhance the curvature adjustment capability of flexure hinges. Theoretical models for the dynamics, compliance, precision, and stress of the bio-inspired single-axis flexure hinge are established based on a discrete-beam transfer matrix. The precision, stress and compliance of the bio-inspired hinge are investigated based on structural parameters, demonstrating its outstanding comprehensive performance through comparative validation. Additionally, dynamic and compliance models of both series-arranged and parallel-arranged two-axis flexure hinges are established, and the optimized structural design is performed. Finally, the proposed theoretical model and parameter optimization design method are verified through an experiment. The proposed bio-inspired flexure hinge and the optimization method provide a new idea for the structural design and performance enhancement of spatial compliant mechanisms.

Under metabolic disorders such as diabetes, the regenerative capacity of bone tissue is compromised, characterized by hyperglycemia-induced oxidative stress, impaired osteogenesis, and dysregulated angiogenesis. These complications undermine the efficacy of conventional bone repair materials, limiting their capacity to promote effective healing. Herein, we developed a metal-flavonoid functionalized coating strategy that integrates osteogenic and angiogenic metal ions with natural antioxidant flavonoids. Leveraging their chelation ability and strong surface affinity, a one-pot approach is established to endow conventional bone repair materials with tailored biofunctions that modulate the diabetic bone microenvironment and facilitate regeneration. Among the tested candidates, copper-quercetin (CQ) coating is screened as the optimal formulation owing to its potent antioxidative, osteoinductive, and pro-angiogenic properties under high-glucose (HG) conditions. Conventional bone repair materials (e.g., β-tricalcium phosphate, β-TCP) modified with this coating significantly ameliorated oxidative stress, restored osteogenesis, and rescued angiogenesis impaired by persistent hyperglycemia. In diabetic rats, CQ-coated β-TCP (β-TCP@CQ) accelerated bone healing by 1.68-fold compared to unmodified controls. Mechanistically, the CQ coating activated the ATP7A/SOD3/FLT1 axis to restore copper homeostasis in bone marrow mesenchymal stem cells while stimulating the PI3K-Akt pathway to enhance osteogenic differentiation. Moreover, the coating exhibited broad versatility across multiple biomaterial compositions (metals, ceramics, polymers, and composites) and structures (2D discs, 3D scaffolds). This metal-flavonoid coating strategy demonstrated feasibility and scalability, while also providing a mechanistic foundation and technical platform for the effective use of conventional bone repair materials in complex pathological contexts.

Intrauterine adhesions (IUAs) are essentially fibrosis of the endometrium within the uterine cavity. It is a common cause of infertility in women and seriously affects their physical and mental health. Current therapeutic strategies have failed to reach satisfactory outcomes. Injectable and self-healing uterine hydrogels with antifibrotic properties would be efficient in preventing IUA. In this work, we prepared curcumin-loaded carboxymethyl chitosan (CMC)–oxidized hyaluronic acid (OHA) intrauterine hydrogel (Cur@CMC-OHA hydrogel) with antifibrotic properties, and its injectable and self-healing properties could be adapted to the morphostructures of the uterine cavity. The hydrogels exhibited tissue adhesive power, which is ideal for stable uterine cavity retention and therapeutic outcomes. In vivo experiments showed that in situ injection of the Cur@CMC-OHA hydrogel into a mouse model of IUA reduced fibrotic tissues, prevented IUA, and improved the reproductive outcomes. It effectively downregulated fibrosis-associated transforming growth factor-β1 (TGF-β1) expression and reversed epithelial–mesenchymal transition (EMT), resulting in anti-fibrotic and fertility restoration. In conclusion, Cur@CMC-OHA hydrogel may be a promising alternative for clinical treatment of uterine adhesion.

Mucin-17 (MUC17) is a transmembrane glycoprotein, expressed on the apical membrane of normal gastrointestinal mucosal epithelial cells, play important roles in preventing infection at mucosal surfaces1-2. MUC17 is a promising target for ADC development due to its highly expressed in gastric, colon and pancreatic cancers, but limit normal organs expression. HDM2012 is a MUC17 targeting ADC, consisting of a topoisomerase inhibitor via a cleavable liker with average drug antibody ratio (DAR) 8. The efficacy and safety of HDM2012 was tested in patient derived xenograft (PDX) models and monkeys, respectively. HDM2012 showed target dependent anti-tumor activity and by-stander effect in vitro. HDM2012 exhibits good efficacy in PDX and CDX models. In gastric PDX models, HDM2012 demonstrated dose dependent efficacy, with TGI (tumor growth inhibition) value of 82-93%, regardless of prior Ironitecan and Top-I ADC treatment. In heavily pre-treated colon cancer PDX models, HDM2012 induced prolonged tumor regression, with TGI value of 94.6%. Furthermore, in MUC17 low expression pancreatic PDX models, HDM2012 could induce sustained tumor regression, with TGI value of 91.5%. In exploratory toxicology study, HDM2012 is well tolerated by cynomolgus monkeys at 45 mpk. Here, we reporting a novel ADC product HDM2012 targeting MUC17, is a potential therapeutic approach for MUC17 positive GC, CRC, PDAC cancer treatment. All the experiment data indicated HDM2012 may be a promising candidate for GI cancer treatment. 1. Gum JR, et al. Biochem Biophys Res Commun.2002;291:466-475. 2. Van Putten JPM, et al. J Innate Immun. 2017;9:281-299. Qinyu Shu, Zhaofeng Qin, Shengxing Zhao, Yang Chen, Kuan Lu, Qian Zhang, Liubin Guo, Qingli Wei, Hao Pan, Yan Xia, Hongwen Li, Dongzhou Jeffery Liu. Translational studies of HDM2012, a novel topoisomerase inhibitor ADC targeting MUC17, in patient derived GC, CRC, PDAC tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 316.

Cadherin 17 (CDH17) is a cell-to-cell adhesion protein that is a member of the cadherin superfamily. CDH17 is frequently overexpressed in colorectal cancer (CRC), gastric cancer (GC) and pancreas cancer (PC)1. HDM2017 ADC comprises a human monoclonal antibody specifically targeting CDH17 and chemically conjugated to CPT-derivative payloads. HDM2017 is undergoing IND-enabling studies. In vitro and in vivo preclinical studies were conducted in the discovery of HDM2017 against gastrointestinal cancers. Initial investigations on plasma stability were performed. Exploratory toxicity assessments were carried out in cynomolgus monkeys and rats. HDM2017 demonstrates excellent cell binding activities with CRC and GC cells, with an EC50 ranging between 0.1-1.0nM. Additionally, HDM2017 exhibits strong target-mediated internalization activities, achieving an internalization efficiency of 43-75%. The HDM2017 ADC displays potent expression-dependent in vitro anti-tumor activity in a range of CDH17 expressing tumor cell lines. Treatment with HDM2017 ADC resulted in significant inhibition of tumor growth in xenograft models of CDH17+ human CRC (71∼97% TGI) and GC (71∼90% TGI). HDM2017 ADC exhibited excellent stability in human, monkey, and rat plasma with a drug shedding rate below 0.5%. Toxicity studies primarily revealed payload-related toxicity profile, which supports further development of the ADC molecule. Analysis using CDH17 IHC assay on patient tissues showed detectable expression of CDH17 in 90% (29/29) cases of colorectal cancer, 70% (7/10) cases of gastric cancer and 65% (13/20) cases of pancreas cancer. HDM2017ADC exhibited potent cytotoxicity in vitro and in vivo anti-tumor activity in various gastrointestinal cancer models. The preclinical activity and safety profile warrants further clinical development with biomarker strategy. Overall, the preclinical data presented here suggests that HDM2017 ADC has the potential to provide clinical benefit to gastrointestinal cancer patients. Chen Lin, Yan Xia, Liubin Guo, Yang Chen, Tingyang Wang, Kuan Lu, Hao Pan, Yayun Zhao, Jie Fang, Hongwen Li, Dongzhou Jeffery Liu. Discovery of HDM2017, a CDH17-targeting ADC for colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 317.

FGFR2b is a novel protein biomarker detected by IHC with the overexpression rate of ∼30% (any 2+/3+) in gastric or gastroesophageal junction cancer(GC/GEJC) patients, and among those patients ∼40% are not eligible for currently approved targeted therapies (HER2, PD-L1, MMR and CLDN18.2)1. HDM2020 is a topoisomerase Inhibitor based DAR8 ADC developed using a novel Ab targeted against FGFR2b, which has the potential to treat FGFR2b overexpressing tumor with reasonable safety window2. Methods: In vivo cell line (CDX) and patient derived xenograft (PDX) models were conducted to validate the therapeutic potential of HDM2020 against GC and sq-NSCLC. FGFR2b expression were detected by IHC using various tumor paraffin sections. Results: Combination of HDM2020 and avastin or paclitaxel demonstrated a synergistic effect in GC CDX model. Single-agent therapeutic activity of HDM2020 was demonstrated in two FGFR2b-positive GC PDX models with TP53 or BCOR gene mutation and at least 1st line chemotherapy. At a dose of 10mg/kg, the maximum tumor growth inhibition rate were 98% and 99%. In FGFR2b middle expressed sq-NSCLC PDX model, complete response was observed at single dose of 10mg/kg. The minimum effective doses were between 2.5-3mg/kg in above three models. FGFR2b is overexpressed in GC, sq-NSCLC, TNBC and may other tumor types. Conclusion: Based on the clinical validation of FGFR2b in GC and signs of early preclinical activity in sq-NSCLC with significant unmet need, HDM2020 might has promising efficacy in these indications. HDM2020 is expected to enter clinical development in 2025. References:1: Seiya Sato, Shannon L Rhodes, et al. Fibroblast Growth Factor Receptor 2 Isoform IIIb (FGFR2b) Protein Overexpression and Biomarker Overlap in Patients With Advanced Gastric or Gastroesophageal Junction Cancer(GC/GEJC). ESMO, 2024.2: Tingyang Wang, Liubin Guo, et al. Development of a novel FGFR2b-targeting ADC with robust anti-tumor efficacy in preclinical evaluation. World ADC SAN DIEGO 2024. Tingyang Wang, Liubin Guo, Kuan Lu, Hao Pan, Yang Chen, Zhaoxing Yu, Yayun Zhao, Shengxing Zhao, Qingli We, Ruizhe Wang, Yan Xia, Hongwen Li, Dongzhou Jeffrey Liu. Preclinical development of HDM2020, a novel ADC targeting FGFR2b, in gastric cancer (GC) and squamous non-small cell lung cancer (sq-NSCLC) xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 245.

Periodontitis, a chronic inflammatory disorder primarily induced by bacterial infection and exacerbated by excessive oxidative stress, leads to the destruction of alveolar bone. Diabetes mellitus intensifies this oxidative stress in periodontal tissues and disrupts the oral microbiome, thereby aggravating periodontal conditions and complicating the management of periodontitis. The development of materials that possess comprehensive therapeutic effects, including antibacterial, antioxidant, and osteogenic properties, for the treatment of diabetic periodontitis (DP) remains at the forefront of research. In this study, we introduced a copper hydrogen phosphate (CuHP) composite hydrogel, which exhibited multi-enzymatic activities at varying pH levels. This hydrogel was synthesized by encapsulating CuHP within a commercially available sodium alginate (SA) matrix. In vitro analyses explored the pH-responsive enzymatic activities, biocompatibility, and the antioxidant, osteogenic, and antibacterial properties of the resultant SA/CuHP composite hydrogel. At neutral pH, the hydrogel primarily exhibited catalase-like activity, providing it with antioxidant capabilities that reduced the inhibitory effects of oxidative stress on osteogenesis in bone marrow mesenchymal stem cells. In mildly acidic conditions, the hydrogel displayed peroxidase-like activity, catalysing the production of more potent reactive oxygen species and exhibiting significant antibacterial efficacy against Aggregatibacter actinomycetemcomitans. Furthermore, the SA/CuHP hydrogel continuously released copper ions, which synergistically enhance its osteogenic and antimicrobial efficacies. In vivo studies demonstrated that this composite hydrogel significantly inhibited bacterial growth and promoted bone regeneration in a rat model of DP. These findings suggest that the SA/CuHP hydrogel holds substantial potential for the treatment of periodontitis in patients with diabetes.

Cardiovascular disease is the leading cause of death worldwide,with myocardial infarction(MI)being a serious threat to human health and life.Current pharmacological and surgical interventions primarily serve as palliative measures,failing to address the root cause of cardiomyocyte death post-MI.Recent advances in regenerative biomedical materials,however,offer promising solutions.Inorganic bioactive materials,capable of interacting with cells and tissues to activate cellular responses and modulate tissue regeneration,have garnered significant attention in regenerative medicine and tissue engineering.Silicate-based biomaterials(e.g.,bioceramics,bioactive glasses),carbon-based nanomaterials,and metal oxides exhibit remarkable potential in promoting myocardial repair and regeneration.This review highlights the latest progress in inorganic bioactive materials for myocardial regeneration and repair,elucidates their material categories and mechanisms of action,and discusses current challenges in clinical translation,while providing insights into future research directions.

BackgroundThe gut microbiota plays a key role in regulating bone homeostasis. Our previous work demonstrated that the novel organic selenium compound β-trifluoroethoxy dimethyl selenide (4aa alleviates osteoporosis; however, its mechanism remains unclear.MethodThe cytotoxicity of 4aa in osteoblast (MC3T3-E1) and osteoclast precursor (RAW264.7) cells was evaluated using CCK-8 assays. Ovariectomized (OVX) and sham-operated mice were treated with various concentrations of 4aa for 8 weeks, including a subgroup pretreated with antibiotics (ABX) to deplete the gut microbiota. Femoral bone structure was assessed by micro-computed tomography (micro-CT), osteoclast numbers were quantified, gut microbial composition was analyzed via 16S rRNA sequencing, and fecal metabolites were profiled using LC-MS/MS.Results4aa concentrations below 20 μM were non-cytotoxic to MC3T3-E1 and RAW264.7 cells. In vivo, 4aa significantly improved femoral bone mass and trabecular microarchitecture in OVX mice. Gut microbiota analysis revealed increased relative abundances of Dubosiella, Akkermansia, and Bacillus spp following 4aa administration. Metabolomic profiling identified marked alterations in citronellal, tyrosol, kaempferol, leukotriene D4, clomipramine, and phenol sulfate level. Moreover, 4aa elevated butyric acid levels and reduced the accumulation of α-ketoisovaleric acid (α-KIV), contributing to the inhibition of osteoclast differentiation.Conclusion4aa prevents estrogen deficiency-induced bone loss by modulating gut microbial composition and function. These findings support the therapeutic of 4aa as a microbiota-targeted therapeutic strategy for osteoporosis management.

Based on the observation of silicon content decrease in the muscles and serum with aging, this study proposes a silicate bioactive material based therapy for treating sarcopenia. Two therapeutic strategies were designed. One utilizes calcium silicate (CS) hydrogel for localized intramuscular treatment, and the other employs CS solution for systemic treatment through Intravenous injection. Both treatments restore silicon levels in the muscles and serum of aging mice, and show therapeutic effects on sarcopenia. Specifically, the CS hydrogel demonstrates more pronounced short-term efficacy in promoting local muscle regeneration, while the CS solution exhibits superior outcomes in modulating the overall condition of aging mice. The fundamental mechanism of the CS treatments on sarcopenia may involve the direct regulation of the SIRTs signaling pathway by silicate ions released from CS, as well as the indirect regulation of SIRTs pathway via the suppression of Sarcolipin (SLN) overexpression by silicate ions. Specifically, silicate ions directly upregulate SIRT1 expression in macrophages and on one side promote NF-kB deacetylation to inhibit M1 polarization, and on the other side facilitate STAT3 deacetylation to inhibit M2 polarization, ultimately reducing the expression of inflammatory factors (TNF-α, IL-6) and fibrotic factors (IL-10, TGF-β). Meanwhile, silicate ions directly upregulate SIRT3 in myoblasts, leading to the promotion of STAT3 dephosphorylation, inhibits mitochondrial reactive oxygen species (ROS) secretion, and enhances the expression of MyoD, MyoG, and Myosin, and accelerates myogenic differentiation. This bioactive CS based therapy provides a new approach for combating sarcopenia.