Intracerebral hemorrhage (ICH) carries high mortality and disability rates, driven not only by the initial bleeding but also by secondary neurotoxicity from blood derived components such as hemoglobin. An effective strategy during the subacute phase must therefore address both hematoma clearance and neuroinflammation. To achieve this dual action therapy, we engineered a novel nanoplatform (M2-exo@HI) by encapsulating a plasmid co-expressing haptoglobin (Hp) and interleukin-10 (IL-10) within M2 macrophage-derived exosomes. Leveraging the innate inflammatory homing of macrophage exosomes, M2 exo@HI delivers the HI plasmid to the ICH site, where it is primarily internalized by M1 microglia. The expressed Hp binds hemoglobin, reducing neurotoxicity and exert neuroprotective effects. Simultaneously, IL-10 polarizes M1 microglia to the neuroprotective M2 phenotype, thereby removing hematoma and alleviating neuroinflammation via anti-inflammatory cytokine production. Consequently, M2-exo@HI significantly reduced hematoma volume, improved long-term neurological function, and enhanced blood-brain barrier (BBB) repair. Transcriptome analysis further elucidated the genetic mechanisms underlying this synergistic effect. This work presents a promising co-delivery strategy for enhancing hemorrhagic stroke therapy.

The increasing prevalence and incidence urge efficient treatment of osteoarthritis (OA). In contrast, a single modality is hard to combat OA's complicated pathogenesis and achieve comprehensive chondroprotective function. Through RNA sequencing, we identified bone marrow mesenchymal stromal cell-derived exosomes (BMSC-Exo) and cartilage progenitor cell-derived exosomes (CPC-Exo) have distinct enrichment of miRNA contents, emphasizing macrophage and chondrocyte modulation, respectively. Thus, inspiring us to develop a bi-exosome combination strategy, which combines anti-inflammatory BMSC-Exo and anti-catabolic CPC-Exo, to alleviate osteoarthritis progression via simultaneous regulation of macrophage polarization and chondrocyte phenotype. Once delivered into the rat knee joint cavity by hyaluronic acid methacryloyl microspheres, the bi-exosome combination remarkably postponed OA progression via combating the joint inflammatory and catabolic environment, in which the dominant interventive pathways (i.e., miR-708–5p/NRP-1, miR-431/BRCA-1/PLK-1, and miR-7a-5p/NOTCH-3) were further revealed. This work presents the tailoring of exosome compositions to modulate multitargeting, thereby creating a potential for OA treatment.

Recent studies have challenged the notion that bone tissue lacks lymphatic vessels, highlighting their essential role in bone regeneration. Effective bone repair relies on the interplay of osteogenesis, angiogenesis, and lymphangiogenesis. Here, we present a three dimensional-printed biomimetic Gelatin methacryloyl/icariin@Mesoporous silica nanoparticle/Hydroxyapatite (GelMA/ICA@MSN/HAp) scaffold designed to recruit bone marrow mesenchymal stem cells (BMSCs), human umbilical vein endothelial cells (HUVECs), and lymphatic endothelial cells (LECs), enabling these cells to self-assemble into "cell islands" that coordinate tissue regeneration. The scaffold exhibits excellent biocompatibility, biodegradability, and sustained cytokine release. In vitro, it promotes the migration, proliferation, and lineage-specific differentiation of BMSCs, HUVECs, and LECs. In an osteoporotic bone defect model, the scaffold significantly enhances new bone formation, supports vascular remodeling by recruiting HUVECs, and induces lymphatic maturation via LECs, accompanied by upregulation of bone morphogenetic protein 2, vascular endothelial growth factor, and prospero homeobox protein 1. Transcriptomic analysis identifies activation of the hypoxia-inducible factor 1 alpha (HIF-1α) signaling pathway as crucial to these effects. Mechanistically, LECs-derived conditioned medium stimulates HUVECs angiogenesis and BMSCs osteogenesis by inducing HIF-1α mediated mitochondrial metabolic reprogramming. This is the first study to integrate lymphatic modulation into scaffold design for bone repair, achieving osteo-angio-lymphogenic coupling and establishing a novel organoid model for bone regeneration.

Ultrasound patches have demonstrated values in non-invasive diagnostics through echo reception, while their therapeutic potentials are restricted by precisely controlling ultrasound energy and integrating multi-effects. Here, we introduce a spatiotemporal acoustic meta-patch (STAMP) that generates controllable heating, mechanical, and biological effects for synergistic multifactorial wound treatment. The STAMP utilizes acoustic metamaterial composites, including reconfigurable interdigital transducers (IDTs) and acoustic impedance matching layer, to focus and transport ultrasound energy with high spatial precision and efficiency. This patch exhibits multiple therapeutic effects, such as localized heating, ultrasound-enhanced bioactive agent delivery and cell migration. Based on these beneficial effects, we show that STAMP can precisely and spatiotemporally regulate wound microenvironments by modulating temperature, inflammation, and wound closure, providing a proof-of-concept for enhanced multifactorial wound healing. We believe that the reconfigurable and multifunctional acoustic metamaterials-based patch may open new possibilities for direct ultrasound-based therapeutics.

Trained immunity refers to a functional reprogramming of the innate immune system that enhances its ability to respond to secondary stimuli. Monocytes and macrophages are central effectors of innate immunity with broad therapeutic relevance. Their capacity to acquire trained immunity enhances host defense and shapes immune homeostasis through epigenetic, metabolic, and functional changes. Unlike previous reviews that primarily focus on molecular mechanisms or vaccine-induced training, this review emphasizes the distinct roles of monocyte/macrophage-mediated trained immunity, originating from both central and peripheral sources. We further discuss how nanomaterials can be harnessed to precisely modulate this process, offering new opportunities for infection control, tumor immunotherapy, and the regulation of chronic inflammatory diseases. This dual-perspective framework provides a foundation for translating trained immunity into targeted clinical interventions.

Hydrogel coatings have become indispensable for advanced interventional devices owing to their exceptional lubricity, antithrombogenicity, and antibacterial performance. However, clinical adoption has been hindered by the risk of polymer embolism resulting from coating delamination in vascular systems. Herein, we report an embolism-free hydrogel coating strategy based on chain-entanglement-mediated topological gelation to address this limitation. Through an interface-regulated polymerization process, we fabricate a robust zwitterionic hydrogel coating stabilized by interfacial interlinking and enhanced polymer chain entanglement. This design delivers outstanding long-term antimicrobial and antithrombogenic properties and achieves high toughness, ultra-low friction, and wear resistance. Notably, the chain-entangled topological hydrogel exhibits a unique fail-safe mechanism: upon detachment, it undergoes spontaneous aqueous dissolution rather than forming hazardous debris. This approach can potentially reduce life-threatening complications in interventional therapies by eliminating the risk of polymer-induced embolism.

Small extracellular vesicles (sEVs) are increasingly regarded as a unique class of bioactive materials whose intrinsic membrane composition and nanoscale architecture provide a versatile platform for therapeutic engineering. Rather than passive carriers, sEVs can be actively programmed through diverse strategies to achieve efficient loading, precise targeting, and functional integration with synthetic systems. Endogenous modulation of donor cells—via genetic editing, priming with bioactive glass, cytokine stimulation, or hypoxic cues—enables selective packaging of nucleic acids, proteins, and metabolites into secreted vesicles. Exogenous techniques, including electroporation, sonication, and extrusion, allow controlled incorporation of therapeutic drugs or genome-editing complexes such as CRISPR/Cas. In parallel, surface modifications based on Lamp2b-fusion scaffolds, aptamers, antibodies, and click chemistry confer tissue tropism and extend circulation time. Integration with nanomaterials, scaffolds, and microfluidic platforms further enhances stability, scalability, and reproducibility, positioning sEVs at the intersection of biology and materials science. This review highlights recent advances in engineering sEVs as programmable bioactive materials and discusses their potential to transform regenerative medicine, oncology, and precision therapeutics.

Skin aging resulting from collagen loss induced by endogenous and exogenous stimuli has become an important factor affecting skin aesthetics and quality of life. The use of simple and efficient soft tissue fillers represents an effective approach to promote collagen regeneration and restore soft tissue support. In this study, mossy-textured hydroxyapatite (CaHA)-modified poly (lactic-co-glycolic acid) (PLGA) composite microspheres (CaHA/PLGA) are developed. These microspheres feature a uniform and stable coating of CaHA beads on the surface of PLGA microspheres and possess particle sizes suitable for soft tissue filling (30–60 μm). The CaHA beads impart a highly porous structure, enhanced protein adsorption, and delayed degradation properties to the composite microspheres. Due to the surface modification by CaHA beads, CaHA/PLGA microspheres exhibit improved cell adhesion, proliferation, and low inflammatory response, as well as enhanced collagen deposition. In vivo studies show that, compared to commercial PLLA microspheres, CaHA/PLGA microspheres provide tissue support as long as 12 weeks with degradation stability, and significantly promote collagen network formation, supporting their long-lasting filling performance. Transcriptome sequencing indicates that CaHA/PLGA microspheres enhance calcium/TGF-β and chemokine signaling pathways in adipose-derived stem cells, facilitating cell migration, cytokine production, and extracellular collagen deposition. Overall, mossy-textured CaHA/PLGA microspheres provide a promising new strategy for soft tissue augmentation and reconstruction.

Cationic modification of hyaluronic acid (HA) is challenging due to its polyanionic nature, poor reactivity in water, and the instability of conventional coupling intermediates. This limits the development of HA-based components in non-viral gene delivery systems, which already suffer from amorphous morphology and mechanical fragility that reduce their transfection efficiency. Here, we reprogram a classically unfavorable EDAC-mediated rearrangement into a productive synthetic route, enabling direct cationization of hyaluronic acid (HA) through spontaneous O-acylisourea rearrangement. This water-based, catalyst-free process achieves up to 70 % substitution of HA's carboxyl groups—introducing cationic tertiary amine functionalities in water. The resulting aminated-hyaluronic acid (HAA) scaffolds act as rigid structural backbones in virus-inspired polymer–DNA nanoparticles termed as “Skeletoplexes”, with enhanced stability and performance. When incorporated into polyplexes formed from diverse cationic systems—including poly(β-amino esters) and commercial vectors such as BrPERfect, Xfect, jetPEI, and Lipofectamine3000—HAA scaffolds improved in vitro transfection efficiency by up to 4-fold and in vivo gene expression by approximately 2-fold. These results establish a generalizable and green scaffold-based strategy that bridges the structural and functional gap between viral and non-viral gene delivery vectors.

Intervertebral disc degeneration (IVDD), a primary cause of debilitating low back pain, is driven by a vicious cycle involving a harsh microenvironment (“soil”) and dysfunctional nucleus pulposus cells (“seeds”), which together promote pathological neurovascular ingrowth (“weeds”) and pain. A therapeutic strategy that can simultaneously “condition the soil” and “modulate the seed” is therefore paramount. Thus, we engineered a biomimetic intelligent nanoliposome (NM-LPTK/RSV-MnCDs) for this dual purpose. The platform is camouflaged with NPC membranes for precise “seed”-homing and incorporates a reactive oxygen species (ROS)-responsive linker for on-demand drug release within the degenerative “soil.” It co-delivers carbonized Mn-containing nanodots (MnCDs) to “condition the soil” by scavenging ROS, and resveratrol (RSV) to “modulate the seed” by suppressing pro-neurovascular signaling. The nanoplatform demonstrated outstanding efficacy in vitro and in two distinct murine IVDD models. It effectively scavenged ROS, inhibited axonal and vascular growth, and preserved matrix synthesis. In vivo, it significantly attenuated disc degeneration, suppressed pathological neurovascular ingrowth, and alleviated pain-related behaviors. Mechanistically, we found this synergistic “soil-conditioning” and “seed-modulating” effect was mediated through the inactivation of the Hippo-YAP signaling pathway, which restored redox homeostasis and blocked aberrant remodeling. This study establishes a targeted, intelligent nanoplatform that synergistically alleviates IVDD and discogenic pain by restoring the disc ecosystem via Hippo pathway inhibition, presenting a precise therapeutic paradigm for degenerative disc disease and its associated neuropathic pain.