Scaffold-guided bone regeneration (SGBR) is an emerging strategy for reconstructing large segmental bone defects, but the biological basis and conditions of its clinical performance remain incompletely defined. In this narrative review, we consolidate a mechanobiological framework that conceptualizes SGBR as the spatiotemporal compartmentalization of the bone-healing cascade, whereby temporary architectures may organize a large defect into multiple, communicating, graft-loaded mechano-transport compartments. Within this nested scaffold-graft-host-fixation system, these compartments are defined by their local mechanical environment, transport properties, and evolving biological composition, which together influence hematoma organization, immune and vascular responses, graft incorporation, osteogenesis, and remodeling. We synthesize fracture and nonunion biology, the diamond concept, interfragmentary-motion theory, scaffold architecture studies, preclinical defect models, and heterogeneous early clinical evidence. Because current clinical evidence consists mainly of case reports and small heterogeneous case series, we interpret these data as feasibility signals. By integrating established mechanisms spatially and temporally, the framework proposes the evolving graft-loaded repair compartment as the mesoscale functional unit of SGBR and yields testable biomaterials design propositions. It proposes that durable regeneration depends on both stage-appropriate local compartment competence and progressive continuity between compartments; accordingly, pore architecture, graft distribution, graft-loaded permeability, surface bioactivity, degradation, wet-state mechanics, and fixation coupling should be evaluated as interacting variables under clinically relevant conditions. Finally, we map these variables to healing stages and technological readiness, identify evidence gaps, and define validation requirements for the implanted patient-specific scaffold-graft construct.

Metal-coordinated DNA nanostructures have emerged as promising drug delivery platforms owing to their rapid synthesis and high loading capacity. However, current systems degrade within two weeks, presumably because uniform coordination poorly resists perturbation, and physiological phosphate displaces metal ions from DNA. Here, we overcome this bottleneck by co-coordinating Fe[2+] and Zn[2+] with DNA to generate heterogeneous networks with locally ordered domains. At an optimized Zn/Fe ratio, the nanoassembly maintains structural integrity for over four months. This month-scale stability moves DNA-metal nanoassemblies beyond freshly prepared formulations, supporting storage, transportation, and on-demand therapeutic applications. Beyond stability, the dual metals deliver orthogonal ferroptosis-directed functions. We engineered a HER-2-targeted nanocomplex (P@H-GDz/Zn/Fe) integrating a Zn[2+]-activated GLUT1-cleaving DNAzyme and a GPX4-inhibitory peptide. Intracellularly, Fe[2+] drives Fenton-like radical generation and mitochondrial stress, while Zn[2+] enables DNAzyme-mediated GLUT1 silencing to restrict glucose influx, impair glutathione regeneration, and preferentially sensitize glucose-dependent tumor cells to ferroptosis. GPX4 inhibition further disables lipid peroxide detoxification, collectively amplifying ferroptosis death. The nanocomplex shows markedly greater cytotoxicity toward gastric cancer cells than normal fibroblasts and demonstrates potent efficacy in both subcutaneous and orthotopic models. This work establishes bimetallic coordination as a route to stable DNA-metal nanoassemblies enabling metabolic-sensitized ferroptosis therapy.

Thrombotic diseases continue to pose a significant clinical challenge with high mortality and recurrence rates following thrombolysis. Herein, we propose endogenous shear stress-activated tribocatalytic thrombolysis via a dynamic S-scheme heterojunction and thrombosis recurrence-prevention via cascade nanozyme catalysis. Specifically, deformable yolk-shell nanoparticles (NPs) composed of bismuth ferrite-coated flexible mesoporous organosilica (fBF) yolks and manganese-doped cerium oxide (CeMn) shells, with fucoidan subsequently grafted onto the surface, are referred to as fBF@CeMn-Fu. Local shear stress induces high-frequency friction and collision between the fBF yolks and the CeMn shells, and tribocatalytic activity is promoted through friction contact area expansion via the deformability of mesoporous organosilica, S-scheme heterojunction between fBF and CeMn, and Mn-O-Ce electron channel and oxygen vacancies in CeMn. These deformability/component engineering and tribovoltaic/piezoelectric effect collectively boost electron-hole separation, overall redox capacity and generation of reactive oxygen species for effective thrombus dissolution. Upon completion of thrombolysis, Mn doping acts as a bidirectional electron pump, accelerating electron transfer and augmenting the superoxide dismutase (SOD) and catalase (CAT) activity of CeMn nanozyme. This SOD-CAT cascade catalysis effectively mitigates oxidative stress and inflammatory microenvironment associated with thrombosis, laying a foundation to prevent thrombosis recurrence. In a carotid artery thrombosis model, combination of tribocatalysis and fucoidan grafting achieve nearly complete thrombus dissolution. Subsequently, nanozyme cascade catalysis restores endothelial function, upregulates nitric oxide synthase expression, promotes endothelial healing, thereby suppressing platelet activation and thrombosis recurrence. The deformable yolks-enhanced tribocatalysis and nanozyme cascade offer an effective strategy for thrombosis management with precise dissolution and recurrence prevention.

Bone repair involves dynamic vascular and lymphatic networks that deliver inductive signals to regulate tissue-specific functions. As an interconnected structure can serve as an essential guide for these vessels, designing a multifunctional biomaterial with fine architecture remains a promising yet challenging frontier in load-bearing bone regeneration. Herein, a novel 3D-printable ink composed of a biodegradable citrate-based polymer and nano-hydroxyapatite (n-HA) is developed to fabricate high-fidelity bionic structures with sub-100 μm resolution. The printed scaffolds demonstrate effective interphase load transfer, achieving high toughness and strength rivaling native bone or conventional composite materials. As an innovative platform for bone regeneration, these scaffolds enable localized loading and sustained release of gastrodin at the target site. Collaborating with osteoinductive citrate and n-HA, the Haversian bone-mimicking scaffolds enhance cellular activity and osteogenic/angiogenic gene expression. In a rabbit critical-sized segmental bone defect model, the scaffolds facilitate rapid osseointegration and robust regeneration while undergoing gradual degradation at an appropriate rate over the long term. Notably, H-type vessels associated with osterix + osteoprogenitors emerge within the advancing frontier of trabecular bone formation inside and around the scaffolds. Concurrently, lymphangiogenesis is observed within the bone tissues, which effectively synergizes angiogenesis and osteogenesis into an "all-in-one" regenerative strategy, thereby highlighting a transformative avenue in tissue engineering. This advanced graft propels the field of bone tissue engineering and holds great translational potential in practical applications.

Glioblastoma multiforme (GBM) remains a formidable therapeutic challenge due to its aggressive behavior, complex biological barriers, and high recurrence rates. Near-infrared II (NIR-II) phototheranostic nanomedicine has emerged as a promising strategy, offering deeper tissue penetration and enhanced photothermal effects for GBM treatment. Herein, we demonstrate an effective molecular design strategy that leverages expanded free space within aggregates to boost non-radiative decay and improve photothermal conversion efficiency (PCE). Based on this approach, we create a nanomedicine using holo-transferrin (holo-Tf) to encapsulate optimized phototheranostic agents (NDA-18). This nanosystem achieves efficient blood-brain barrier (BBB) penetration via transferrin receptor (TfR)-mediated transcytosis and selective tumor accumulation. Upon 808 nm laser irradiation, the nanomedicine enables precise photothermal therapy (PTT) while concurrently triggering ferroptosis. This ferroptosis process further enhances the PTT efficacy by suppressing heat shock proteins (HSPs), resulting in an enhanced synergistic antitumor effect. Remarkably, this one-step self-assembled nanomedicine integrates five critical functions: from BBB penetration and tumor targeting to dual-mode imaging and synergistic PTT-ferroptosis therapy. In conclusion, we have successfully developed an innovative nanoplatform that unites rational molecular design, bioengineering, and synergistic therapy for GBM treatment.

Epigenetic reprogramming of somatic cells into pluripotent cells provides a versatile and ethical methodology to create patient-specific pluripotent stem cells (iPSCs) for use in regenerative medicine. The Cohesin complex is a vital component that is needed to maintain the 3-dimensional structure of the genome. The formation of transcriptional activation chromatin loops represents a critical epigenetic step on the road to pluripotent reprogramming. To explore the Cohesin chromatin architecture, we performed RNA immunoprecipitation sequencing to profile the long noncoding RNAs (lncRNAs) that interact with Cohesin SMC1 differentially during reprogramming. We identified Silnr1 as a novel reprogramming-associated lncRNA, which is not only a critical component of the Cohesin SMC1 complex, but is also specifically activated during the induction of pluripotency. Silnr1 knockdown triggered stem cells to exit from pluripotency, while induced overexpression of this lncRNA promoted pluripotent reprogramming of fibroblasts. Using RNA reverse transcription-associated trap sequencing (RAT-seq) to profile the genome-wide binding target interaction network, we demonstrated that Silnr1 bound to both the Oct4 (Pou5f1) promoter and enhancer, where it recruited SMC1 and orchestrated a functional intrachromosomal loop that is needed for the establishment of induced pluripotency. These data reveal a previously uncharacterized regulatory pathway, in which lncRNA Silnr1 acts as a chromatin factor to help overcome epigenetic bottlenecks on the path to stem cell reprogramming.

Catalytic nanomedicines face a persistent trade-off between structurally defined active sites and rapid synthesis. A microwave-assisted salt-flux conversion is developed that transforms a bimetallic metal-organic framework precursor within 3 min into nitrogen-doped carbon-supported ZnMn dual-atom nanozymes (ZnMn DAzymes). Aberration-corrected HAADF-STEM and dual-edge X-ray absorption fine structure analyses support adjacent Zn-Mn sites with an N-dominated ZnMn-N6-like coordination motif. Steady-state kinetics and density functional theory calculations suggest cooperative catalysis: Zn modulates H2O2 adsorption and O-O bond activation, whereas Mn provides stronger H2O2 chemisorption and redox flexibility, jointly enhancing catalase-, peroxidase-, and oxidase-like activities. The resulting cascade decomposes H2O2, relieves hypoxia, generates reactive oxygen species, and depletes glutathione, inducing mitochondrial dysfunction, immunogenic cell death, cGAS-STING-associated signaling, dendritic-cell maturation, and effector T-cell infiltration. Glutathione-responsive Mn[2+] release additionally enables activatable T1-weighted magnetic resonance contrast. Combined with αPD-L1, ZnMn DAzymes suppress primary and distal tumors by approximately 90%, reduce lung metastases by 92%, and prolong survival in 4T1 models. This work provides a rapid route to ZnMn dual-atom nanozymes for catalytic immunotherapy.

Gut microbiota modulates gut-brain crosstalk in Parkinson's disease (PD), yet effective therapies are still lacking. Herein, we report an orally administrable microalgae-nanozyme platform (SP@SKCN) via combining sulfur/potassium (S/K) co-doped carbon nitride (SKCN) with Spirulina platensis (SP), offering a novel therapeutic strategy for PD. Uniform S-K co-doping significantly narrows the bandgap of carbon nitride (2.2 eV), endowing SKCN with high near-infrared (NIR)-photocatalytic activity and a star-shaped network morphology, realizing NIR-driven water splitting for H2/O2 generation. Meanwhile, SKCN exhibits superoxide dismutase (SOD)/catalase (CAT) mimetic enzyme activities, efficiently scavenging reactive oxygen species (ROS) and synergistically alleviating inflammation. SP incorporation protects SP@SKCN from gastric acid degradation, prolongs its intestinal retention time, and mediates sustained SKCN release. Notably, SP@SKCN remarkedly improves motor deficits, gastrointestinal dysfunctions, and dopaminergic neuron loss in PD mice. 16 S rRNA sequencing and targeted metabolomics reveal that SP@SKCN treatment reverses both PD-associated microbiota changes and the MPTP-induced reduction in indole-3-lactic acid (ILA). Further experiments indicate that SP@SKCN alleviate intestinal inflammation and gut barrier disruption, consequently attenuating systemic inflammation. Mechanistically, SP@SKCN restore the ILA/aryl hydrocarbon receptor (AHR)/NF-κB signaling caused by disturbed gut microbiota mediated the glial cells activation, which eventually reduce dopaminergic neuron death. Collectively, SP@SKCN ameliorates PD via regulating the microbiota-ILA-brain axis.

Silicosis remains therapeutically intractable because its three driver axes-the NLRP3 inflammasome, ROS/Nrf2 oxidative stress, and TGF-β/Smad fibrosis-interlock into a self-reinforcing network whose topological redundancy reroutes signalling around any single-target drug, the structural basis for repeated single-agent failure. Existing nanocarriers cannot meet the resulting demand for multi-cargo delivery: lipid nanoparticles risk triggering NLRP3, polymeric carriers escape endosomes too poorly to deliver nucleic acids, and inorganic particles intensify the ROS-driven fibrotic loop. Engineered exosomes close this gap. Their native architecture matches the silicotic microenvironment and can carry nucleic acids, proteins, and small molecules together at defined ratios across the vesicle population, while surface CD47 can confer immune evasion, donor-encoded integrins can direct cell-selective pulmonary tropism, and membrane fusion can deliver payloads directly into the cytoplasm, - properties we argue must be demonstrated for each engineered construct rather than assumed. Here, we evaluate the complete engineering pipeline - donor-cell selection, GMP-compatible isolation, cargo loading by electroporation and bio-orthogonal surface click chemistry, and stimuli-responsive release whose triggering thresholds have been established in oncological rather than fibrotic settings and require validation in silicosis. Preclinical evidence, graded by a three-tier scheme, is consistent with coordinated multi-axis efficacy spanning NLRP3 suppression, Nrf2 restoration, and TGF-β/Smad blockade, but remains predominantly Grade B and C; we critically appraise manufacturing scalability, co-loading optimization, and endotype-matched dosing as the milestones still separating this platform from clinical deployment.

Fluoropharmacology integrates pharmacokinetics/pharmacodynamics with real-time visualization by employing intrinsically fluorescent drugs that combine therapy and luminescence in a single entity. Herein, we report the systematic characterization that clinically approved quinolone antibiotics exhibit intrinsic aggregation-induced emission (AIE) characteristics. Mechanistic studies reveal that the AIE behavior originates from restricted intramolecular motion, thereby establishing the "drug-probe unity" principle that a single molecular architecture inherently encodes pharmacological activity, fluorescence emission, and photosensitizing capability. Exploiting this intrinsic property, we strategically repurpose the historically problematic phototoxicity of quinolones into a theranostic advantage by developing them as photosensitizers for localized antimicrobial therapy. This approach enables visualized pharmacokinetics/pharmacodynamics, synergistic antibacterial efficacy combining intrinsic antibiotic action with photodynamic effects against resistance and systemic toxicity through confined topical application. Beyond elucidating the AIE mechanisms of quinolones, this work proposes Fluoropharmacology as a promising framework that could potentially reshape drug discovery and utilization. By revealing that countless existing and future fluorescent drugs possess untapped visualization capabilities, Fluoropharmacology transforms conventional pharmacopeia into intelligent, image-guided theranostic agents, enabling observation of molecular events within living systems, illuminating the once-invisible journey of drugs from administration to action, and ultimately advancing personalized precision medicine that safeguards human health, where every fluorescent molecule narrates its own healing story.

Bone healing is often compromised by comorbidities, limiting treatment success as can also be seen in the elderly. Current treatments, including autologous and allogeneic bone grafts, are associated with drawbacks. Synthetic biomaterials, particularly calcium phosphate (CaP) ceramics, show promise due to their chemical resemblance to the mineral part of native bone but are limited by suboptimal mechanical properties in the context of bone regeneration. Composite scaffolds combining CaP with polymers, such as poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymers offer improved mechanical performance. Zn enhances bone formation and Cu/Co vessel formation. Therefore, to enhance osteogenic and angiogenic potential, we developed βTCP-PEOT/PBT scaffolds doped with Zn, Zn/Cu, or Zn/Co at low (15 mM) or high (45 mM) concentrations. The composites were created by combining βTCP with PEOT/PBT copolymer in a 1:1 ratio. These composites were additively manufactured into three-dimensional (3D), porous scaffolds using 3D fiber deposition techniques and have previously shown mesenchymal stem cell (MSC) differentiation and angiogenesis in vitro without external stimulants. To assess the in vivo response, we implanted the scaffolds intramuscularly in a mini-pig model for 12 weeks. All animals remained healthy, and explanted scaffolds exhibited vascularized, loose connective tissue infiltration. While no mature bone was observed at this time point, extracellular matrix (ECM) deposition was evident in all composite scaffolds but absent in polymer-only controls. Histological analysis showed ECM deposition alongside alkaline phosphatase activity, osteoclast-like cells, and macrophages, with composite scaffolds showing more consistent staining for these markers. These findings suggest an early biological response to ion-doped composite scaffolds potentially favorable to bone regeneration.

Cardiovascular stents are life-saving interventions for occlusive vascular diseases, yet current designs such as drug-eluting stents suppress restenosis via universal antiproliferation, inevitably impairing endothelial regeneration and raising the risk of late thrombosis. Here, we introduce a bioinspired endothelial-selective peptide self-assembling nanofibrous coating (ECSP-SANC) that integrates extracellular matrix (ECM)-mimetic β-sheet nanofibrous topography with REDV (Arg-Glu-Asp-Val)-mediated endothelial recognition cues to create a regenerative stent interface. ECSP-SANC forms a highly hydrated three-dimensional nanofibrous network that recapitulates key architectural features of native ECM while displaying accessible REDV motifs to preferentially promote endothelial cell adhesion, migration, proliferation, and functional maturation. In parallel, the coating suppresses smooth muscle cell overgrowth and synthetic phenotypic switching, thereby conferring an endothelial competitive advantage on the stent surface. The hydrated nanofibrous interface also minimizes platelet adhesion and inflammatory responses, contributing to improved hemocompatibility and local immune regulation. In a rabbit iliac artery implantation model, ECSP-SANC-functionalized stents accelerated re-endothelialization, suppressed neointimal hyperplasia, and effectively prevented restenosis. This approach demonstrates that precise integration of endothelial-selective biochemical signals with ECM-mimetic architecture can orchestrate vascular repair beyond conventional antiproliferative strategies. ECSP-SANC represents a versatile, next-generation platform for regenerative stent coatings, offering a blueprint for cardiovascular therapies that harmonize anti-restenotic efficacy with rapid endothelial recovery.

Hypoxia-activated theranostic agents (HATAs) represent a promising strategy for selective visualization and treatment of hypoxic tumor cells. However, their therapeutic efficacy is restricted by limited tumor-targeting capability, inefficient theranostic agent activation and immunosuppressive microenvironment. Herein, we report a borate-functionalized hypoxia-activatable theranostic agent (AHD-BA) and its application in targeted tumor photo-chemoimmunotherapy. This theranostic agent integrates a NIR-activatable photosensitizer (PS) and a chemotherapeutic drug via an arylazo linker, as well as a boronic acid ester (BAE) moiety that captures NADH to facilitate hypoxia-triggered drug release and significantly enhance tumor-targeting capability. AHD-BA undergoes azoreductase (AzoR)-mediated activation with significantly faster release kinetics compared to its BAE-lacking counterpart (AHD), enabling more efficient consumption of NADH and liberation of both chemotherapeutic agent and PS. Importantly, AHD-BA showed significantly enhanced (55.8-fold) NIR fluorescent intensity in tumor region than AHD. Furthermore, AHD-BA exerted significant anti-tumor effects via inducing mitochondrial dysfunction, mtDNA leakage and energy metabolism disruption, which activated apoptosis and pyroptosis via caspase-3 mediated pathways and ultimately potentiated robust anti-tumor immunity with negligible side effect. This work presents a uniform design strategy with the dual capability of enhancing hypoxia-activated theranostic agent release and enabling its tumor-targeted photo-chemoimmunotherapy.

Spatially controllable modulation of the tumor microenvironment (TME) plays the key role in achieving effective tumor therapy, but the effective regulation of its characteristic biomarkers remains a formidable challenge. In this work, we leverage non-invasive and highly penetrative external ultrasound to modulate the crucial characteristic biomarker hydrogen peroxide (H2O2) within the TME. To achieve this goal, we designed a distinct piezo-self-Fenton nanocatalyst (Fe-doped Bi12O17Cl2) to facilitate in situ H2O2 generation followed by a sequential Fenton reaction that converts locally generated H2O2 into highly cytotoxic hydroxyl radicals (•OH). Under exogenous ultrasound irradiation, the Bi12O17Cl2 piezocatalyst triggers a specific piezoelectric effect to produce H2O2, effectively elevating the typically deficient H2O2 level in the TME. Subsequently, the Fe[2+] dopants within the crystalline lattice of the same Bi12O17Cl2 nanosheets mediate the Fenton reaction to convert the initially generated H2O2 into •OH, thereby enabling a robust cascade catalytic tumor therapy. Systematic in vitro and in vivo results demonstrate that this sequential catalytic design allows for spatially controllable, ultrasound on-demand modulation of the TME biomarker H2O2, catalyzing the production of a large amount of •OH radicals and eliciting superior antitumor efficacy. This proposed piezo-self-Fenton catalytic strategy establishes a representative paradigm on ultrasound-mediated sonocatalytic methodology for TME-modulating cancer therapy.

Radioimmunotherapy is increasingly recognized as an immune-activating modality. However, its therapeutic efficacy in hepatocellular carcinoma (HCC) remains unsatisfactory. Herein, a hyaluronic acid (HA)-modified, HCQ-loaded ZIF-8@MnOx nanoplatform (HCQ@ZIF-8@MnOx@HA, CZMH) is engineered to induce autophagic stress for enhanced radioimmunotherapy. CZMH was synthesized via a ZIF-8 based coordination-driven self-assembly strategy, followed by MnOx deposition, hydroxychloroquine loading, and hyaluronic acid surface modification. CZMH induces pronounced autophagic stress through concurrent autophagy initiation and autophagic flux blockade. CZMH activates cGAS-STING signaling by preventing STING degradation and mitochondrial DNA clearance. By amplifying reactive oxygen species generation and mitochondrial dysfunction, CZMH robustly induces immunogenic cell death. Cytokine release from CZMH-treated cells contributes to reprogramming of the tumor immune microenvironment. When combined with radiotherapy, CZMH markedly enhances tumor control by amplifying tumor-intrinsic damage and radiotherapy-driven immune activation. CZMH potentiates the abscopal effect of radiotherapy by increasing infiltration and activation of CD8[+] T cells in distant tumors and sustaining systemic antitumor immunity. The triple therapy of immune checkpoint inhibitor, CZMH and radiotherapy achieves a pronounced synergistic therapeutic benefit. Collectively, this work establishes CZMH as a potent radio-sensitizing and immunomodulatory nanoplatform to improve therapeutic outcomes in liver cancer treatment.