ABSTRACT Osteoarthritis (OA) is a common age‐related degenerative joint disorder with no effective disease‐modifying drugs. Cellular senescence and mitochondrial dysfunction that disrupt chondrocyte homeostasis are key drivers of OA initiation and progression. Here, we develop mitochondria‐targeted supramolecular nanoparticles (EG NPs) self‐assembled from Epigallocatechin‐3‐gallate (EGCG) and L‐Glutamic acid (L‐Glu), enabling efficient scavenging of mitochondrial reactive oxygen species (mtROS) through targeted delivery and ultimately restoring mitochondrial homeostasis. This leads to reduced DNA damage, inhibition of the NF‐κB inflammatory signaling pathway, and attenuation of cellular senescence along with its associated inflammatory senescence‐associated secretory phenotype (SASP). Simultaneously, mitochondria‐targeted EG NPs promote mitochondrial inner and outer membrane fusion and biogenesis by upregulating fusion markers and activating the AMPK pathway, enhancing energy supply, alleviating cellular senescence, and promoting matrix synthesis in chondrocytes. In vivo experiments in a mouse OA model prove that EG NPs markedly suppress synovial inflammation, alleviate articular cartilage damage and matrix degradation, and ameliorate abnormal subchondral bone remodeling, thereby preserving cartilage structural integrity and effectively slowing OA progression. This multifunctional mitochondria‐targeted nanoplatform, centered on restoring mitochondrial homeostasis, precisely modulates the function of senescent chondrocytes and alleviates their senescent phenotype, establishing a promising new paradigm for OA therapy and opening new avenues for nanotechnology‐based interventions in aging‐related diseases.
ABSTRACT As in vitro tissue models, including organoids, become thicker and more complex, diffusion‐limited three‐dimensional (3D) culture increasingly fails to sustain long‐term viability, nutrient supply, and spatial microenvironmental regulation. Existing vascularization, perfusion, and chip‐based strategies still struggle to integrate complex 3D architecture, durable perfusion, mechanical integrity, and controlled trans‐wall exchange in thick constructs. Here, a fibril‐reinforced, 3D‐printed solid‐walled zein vascular interface is developed to couple long‐term perfusion stability with wall‐mediated mass transport. Homologous zein fibrils enable direct printing of branched perfusable conduits with tunable porous walls, avoiding sacrificial hollow‐channel templating while improving deformation resistance and preserving permeability during 30 days of continuous perfusion. Wall architecture establishes two application‐specific transport regimes. In a regulated‐exchange regime, the interface supports nutrient delivery in 33 × 21 × 11 mm cell‐laden constructs, maintaining long‐term survival and enhancing CD31 expression within a continuously perfused peri‐conduit microenvironment. In a high‐permeability regime, enlarged porous walls generate spatial transport gradients, distance‐dependent heterogeneity, and enhanced permeability and retention (EPR)‐relevant trans‐wall nanocarrier transport with peri‐conduit accumulation, enabling evaluation of photoresponsive liposomal delivery and polyaniline‐mediated photothermal responses. This zein platform integrates printable biomaterial architecture, perfusion durability, and tunable wall‐mediated transport for thick tissue support and EPR‐relevant therapeutic evaluation in advanced in vitro model systems.
ABSTRACT Healing of osteoporotic bone defects is profoundly compromised by the dysregulation of bone remodeling homeostasis, characterized by excessive osteoclastic resorption and diminished osteoblastic activity, thus conventional bioinert bone cements fail to modulate these aberrant conditions or restore physiological remodeling. To address this, alendronate‐conjugated citrate‐based composite microscaffolds, consisting of an alendronate (ALN) conjugated poly (octamethylene citrate) prepolymer mixed with hydroxyapatite (HA) (APOC‐HA), was developed followed by thermal post‐polymerization. Benefiting from the novel composite cylinder fabrication process using powder compression method in a custom‐designed three‐part split mold, and the chelation interaction between ALN and HA, the compression strength of the nonporous composite cylinders exceeded 250 MPa. Upon implantation, ALN conjugated on the polymer chains effectively inhibits osteoclast activity as the material degrades. Simultaneously, the sustained release of citrate, a key metabolic regulator, enhances the energy metabolism of bone marrow mesenchymal stem cells (BMSCs) via participating tricarboxylic acid (TCA) cycle, promoting osteogenic differentiation and mineralization. The crosslinked APOC‐HA scaffold provides robust mechanical support and excellent biocompatibility while improving bone homeostasis. Consequently, this dual‐functional biomaterial offers favorable conditions for regeneration in osteoporotic defects, representing a promising strategy for future clinical applications.
ABSTRACT Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation within joints, where macrophage‐driven inflammatory cascade caused by mitochondrial dysfunction significantly contributes to the pathogenesis. Through recruitment and activation of neutrophils from circulation, these macrophages promote the release of neutrophil extracellular traps (NETs) and generation of reactive oxygen species (ROS), leading to synovitis exacerbation and tissue damage. To disrupt this closely linked cycle, we present a mitochondria‐modulating nanosystem (NM@APDAase) targeting the inflammatory cascade for RA immunotherapy. The neutrophil membrane‐camouflaged nanomaterials are directed to inflamed joints, where the released AP39 effectively restores mitochondrial function by serving as a mild electron donor and uncoupler. This reprograms macrophages from a pro‐inflammatory to an anti‐inflammatory phenotype, thereby eliminating the primary source of inflammation. Notably, the co‐loaded DNase I and polydopamine scaffold work synergistically to clear pre‐existing NETs and scavenge ROS. In vivo studies demonstrate that NM@APDAase significantly alleviates RA pathology as evidenced by reduced inflammatory responses, mitigated cartilage erosion and reduced bone destruction. Our work highlights the promise of mitochondria‐modulating nanomaterials for treating RA through directed disruption of the inflammatory cascade.
ABSTRACT Myocardial infarction (MI) induces ventricular dysfunction through ischemic necrosis and fibrotic remodeling, progressing to heart failure and constituting a major global cardiovascular burden. To address this, we developed a photocurable, hydrogel‐based cardiac patch (Gel‐CS/FMN@LNP hydrogel) with favorable mechanical robustness. The patch is composed of methacryloylated carboxymethyl chitosan (CACSMA) and methacryloylated gelatin (GelMA), incorporating Formononetin‐loaded lipid nanoparticles (FMN@LNPs) for myocardial restoration. In vitro studies demonstrated that the Gel‐CS/FMN@LNP hydrogel not only inhibited cardiomyocyte apoptosis by scavenging reactive oxygen species (ROS) but also promoted migration and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, when a co‐culture system of the Gel‐CS/FMN@LNP hydrogel and heart‐forming organoids (HFOs) was subjected to oxygen‐glucose deprivation (OGD) conditions, the system effectively inhibited HFO apoptosis and suppressed HFO fibrosis. In vivo experiments in MI model rats revealed that the Gel‐CS/FMN@LNP hydrogel group preserved a higher left ventricular ejection fraction (LVEF: 67.2 ± 1.9%) compared to the MI group (LVEF: 41.7 ± 4.7%) at 28 days post‐MI, thereby improving cardiac function. Histological analysis showed that the Gel‐CS/FMN@LNP hydrogel reduced myocardial fibrosis in the infarct border zone, promoted angiogenesis, and facilitated macrophage polarization toward the M2 phenotype. RNA sequencing (RNA‐seq) identified pathways associated with metabolic regulation (PPAR signaling pathway), myocardial protection (PI3K‐Akt signaling pathway), anti‐fibrosis (inhibition of extracellular matrix remodeling), and anti‐inflammatory immune regulation (TNF signaling pathway). Single‐cell RNA sequencing (scRNA‐seq) revealed that the Gel‐CS/FMN@LNP hydrogel promoted post‐MI cardiac repair through a multi‐target network involving circadian rhythm remodeling, matrix regulation, immune balance, and vascular protection. Our hydrogel system, which combines facile injectability, sustained release of active factors, and synergistic therapeutic effects, represents a promising therapeutic approach for post‐MI repair.
