Myopia remains a major global ophthalmic challenge, as existing interventions can slow but rarely halt disease progression or reverse the underlying pathological remodelling. Recent advances in bioelectronics, nanotechnology and neuroengineering have enabled the development of self-powered bioelectronic interfaces for precision ophthalmic therapy. This Review discusses triboelectric and piezoelectric nanogenerators for restoring vision pathways and regulating ocular homeostasis. Key mechanisms underlying myopia progression, including retinal neurotransmission imbalance, scleral remodelling and aberrant visual feedback signalling, are summarized to establish a mechanistic framework for bioelectronic intervention. The therapeutic and diagnostic potential of multifunctional bioelectronic platforms for ocular modulation, targeted drug delivery, controlled release and real-time sensing is then examined. The integration of wearable and implantable ophthalmic devices with artificial intelligence and closed-loop regulation is further highlighted. To provide broad engineering and translational perspectives, representative ophthalmic bioelectronics,such as wireless contact lenses and photovoltaic retinal prostheses-are discussed as architectural reference models. Finally, major translational challenges including long-term biocompatibility, device miniaturization, energy stability and regulatory considerations, are discussed. These next-generation biointerfaces may enable adaptive neuromodulation, real-time visual decoding and seamless integration with digital therapeutics, establishing a new paradigm for precision ophthalmology and functional vision restoration.
Myocardial ischemia/reperfusion (MI/R) injury exposes the heart to a sequential surge of oxidative stress and sterile inflammation, driving maladaptive remodeling and lethal arrhythmias. However, the human-specific mechanisms linking post-ischemic inflammation to electromechanical dysfunction remain poorly defined. Here, we established a human Two-Hit model using human umbilical vein endothelial cells (HUVECs), human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and three-dimensional heart organoids (hHOs). This system integrates acute oxidative priming with the secretome generated by macrophages undergoing secondary necrosis (SN-Sec), thereby recapitulating a redox-active sterile inflammatory microenvironment relevant to the post-ischemic heart. The Two-Hit stress elicited striking cell-type-specific responses. HUVECs exhibited NF-κB activation, exhaustion of inducible antioxidant defenses, and irreversible cell death. In contrast, hiPSC-CMs survived oxidative and inflammatory stress but underwent maladaptive remodeling characterized by stress-induced cytoskeletal remodeling and disruption of gap junction integrity. Mechanistically, sterile inflammation was accompanied by a critical imbalance in calcium handling through selective accumulation of phospholamban (PLN) without a concomitant reduction in SERCA2a expression. The consequent stoichiometric shift markedly correlated with calcium decay kinetics and induced diastolic dysfunction. In hHOs, high-speed optical mapping revealed profound electromechanical discordance, where preserved electrical automaticity became uncoupled from delayed calcium cycling, creating a highly arrhythmogenic substrate. Collectively, these findings identify the ROS-sterile inflammation-PLN axis as a prominent molecular feature correlated with post-ischemic diastolic failure and arrhythmogenesis in human cardiac models. This Two-Hit platform provides a robust framework for dissecting inflammation-driven cardiac remodeling and for evaluating therapeutic strategies targeting post-ischemic electromechanical dysfunction.
Bombyx mori silk is a natural ultra-long protein fiber with a unique structure and extensive applications. Boosting production efficiency and innovating fiber performance represent critical industry needs as well as major technical bottlenecks. In this study, the mutant of the circadian negative regulator period (per) showed increased cocoon silk yield and fibroin content by 19.51% and 9.19%, respectively, and reduced silk fineness by 17.53%. Along with increased crystallinity and molecular orientation of fibroin fibers, the tensile strength and toughness of mutant cocoon silk were improved by 50.59% and 46.75%, respectively. Mechanistic analysis revealed that the per mutant displayed enhanced posterior silk gland development and fibroin synthesis, thereby increasing cocoon silk yield, particularly fibroin production efficiency. In parallel, the per mutant showed enhanced γ-aminobutyric acid (GABA)ergic signaling in the brain of its mature larvae, which was associated with suppressed downstream corazonin secretion and accelerated silk spinning. These findings in the per mutant suggest a promising strategy for targeting the circadian system to enhance fibroin production efficiency and mechanical properties of cocoon silk in B. mori.
The recapitulation of the physiological cellular composition, 3D structure and mechanics of the human myocardium is key to improving the biofabrication of cardiac tissues. To advance the development of engineered heart patches, with significant potential for human cardiac repair, we assessed the impact of their cellular and extracellular constituents on tissue organization and function, by using advanced biofabrication and next-generation sequencing technologies. Combining melt electrowriting (MEW) fibrillary scaffolds with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts (-CFs), we generated human engineered cardiac tissues (MEW-hECTs) by casting in two different biomaterial compositions (fibrin and gelatin-methacryloyl (GelMA)), and varying proportions of the cardiac constituent cells. Under the conditions tested, fibrin-hECTs displayed improved tissue formation, coordinated contraction, structural organization, and electrophysiological behavior compared with GelMA-hECTs. Transcriptomics analysis indicated that fibrin-hECTs exhibited an increase in maturation-associated gene expression signatures compared with GelMA-hECTs, whereas a longer remodeling process of the synthetic environment was required in GelMA. Surprisingly, within the investigated MEW-based composite system, the inclusion of CFs had no positive impact on tissue organization and impaired the electrophysiological properties of myocardial constructs, increasing susceptibility to arrhythmias in computational simulations calibrated with experimental electrophysiological data. This information will help devise advanced myocardial tissues by enabling a comprehensive assessment of the main components, ultimately reflecting the unique native cardiac 3D organization.
Radiotherapy (RT) remains a cornerstone in lung cancer treatment, but its efficacy is often limited by radioresistance and an immunosuppressive tumor microenvironment (TME). Here, we identify the deubiquitinating enzyme USP8 as a key regulator of M2-like tumor-associated macrophages (TAMs) in the irradiated TME. To exploit this finding, we developed a biomimetic nanoparticle, USP8@CPMOF, which co-delivers a USP8 inhibitor and an anti-PD-L1 nanobody-coated membrane. This nanosystem specifically targets both irradiated tumor cells and TAMs, responding to the acidic and high-glutathione TME to trigger ferroptosis and release the USP8 inhibitor. In vitro, USP8@CPMOF enhanced RT-induced apoptosis and ferroptosis, promoted dendritic cell maturation, and reprogrammed M2 macrophages toward an M1 phenotype. In vivo, it improved tumor accumulation, synergized with RT to suppress tumor growth and metastasis, and robustly remodeled the TME by increasing cytotoxic T cell infiltration and reducing immunosuppressive cells. This work presents a promising nanomedicine strategy to overcome radioresistance by simultaneously targeting tumor cells and the immunosuppressive TME.
Circulating tumor cells (CTCs) sensing the chemokine CXCL12 and invading hyaluronic acid hydrogel (CXCL12 loaded hydrogel, CLG) might display metastatic attitude. CLG recovered-human lung (H460, A549), and ovarian cancer cells (IGROV-1) overexpressed the CXCL12 receptor, CXCR4, developed larger spheres and activate transcriptional programs of invasion and stemness. Interestingly, CLG-U87 glioblastoma cells highly expressed EpCAM and significantly upregulated the very specific NGFR, NTS, AQP1 and CMKLR1 genes, associated with cell proliferation, migration/invasion and metastasis. In a syngeneic model, subcutaneous CLG significantly attracted GFP-Lewis lung carcinoma (LLC) cells impairing lung colonization within four hours from cell injection and up to twenty-one days. In lung, M1 macrophages rapidly increased post cancer cells injection while M2 prevailed after 10 days (T10). Neutrophils (Ly6Ghigh and Ly6Glow) infiltrated the lungs after ten days from cells injection with late expansion of immature Ly6Glow. According to lung niche, Empty gel (EG) and CLG were early infiltrated by macrophages and later by neutrophils. CLG generated an immunosuppressive environment defined by M1/M2/Ly6Glow able to capture and divert metastatic CTCs from the lung colonization.
Melanoma's aggressiveness and therapeutic resistance highlight the need for innovative strategies. This study developed a CRISPR/Cas9 ribonucleoprotein (RNP) system targeting the oncogenic YB-1 gene, combined with doxorubicin (DOX), delivered by chondroitin sulfate (CS)-based microneedles (MN) incorporating designed nanoparticles (CNPs). YB-1, a critical oncogene driving melanoma progression, metastasis, and drug resistance, was targeted to enhance therapy efficacy. In vitro experiments demonstrated that CNPs enhanced cellular uptake efficiency, achieving a dual-drug delivery rate of 74.4% and mediating 65.32% gene editing efficiency. The application of CNPs@DOX@RNP reduced tumor cell viability to just 3.51%, while simultaneously lowering off-target toxicity. In vivo C57BL/6 melanoma models showed significant tumor growth inhibition, increased apoptosis, and suppressed proliferation/angiogenesis. Following treatment with CNPs@DOX@RNP/MN, tumor weight exhibited a 92.56% reduction relative to the untreated control. Biocompatibility assays confirmed safety with minimal organ damage. This MN platform offers a synergistic, safe, and effective strategy for combined YB-1 gene editing and chemotherapy, addressing melanoma's therapeutic challenges.
Engineering articular cartilage with hierarchical architecture and effective interfacial integration remains a major challenge. Although bottom-up spheroid assembly offers a promising biofabrication strategy, how chondrogenic maturation influences spheroid fusion and boundary remodeling remains incompletely defined. Here, we investigated differentiation stage as a programmable determinant of the phenotype and assembly behavior of mesenchymal stem cell (MSC)-derived chondrogenic spheroids. Exploratory RNA-seq pathway mapping, complemented by biologically replicated RT-qPCR, indicated stage- and cell-source-associated differences in cartilage matrix and maturation-related programs in bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs). Early-stage spheroids exhibited greater fusion capacity than mature spheroids, whereas incorporation of undifferentiated MSCs promoted the integration of mature chondrogenic spheroids and reduced persistent inter-spheroid boundaries. Sequential assembly of Day-3, Day-7, and Day-14 spheroids generated hierarchical constructs with stage-associated regional differences in cartilage extracellular matrix deposition. Incorporating an undifferentiated MSC layer at the bone-facing interface further supported structural continuity with a porous bone substitute in vitro. In an exploratory porcine pilot study involving two animals, implantation of MSC-derived spheroid grafts into cartilage defects was technically feasible. At 6 months, the repair tissue exhibited variable proteoglycan staining and heterogeneous collagen type II immunoreactivity, while selected sections showed tissue apposition at the graft–host interface. The limited animal-level sample size precluded conclusions regarding repair efficacy, cartilage quality, or superiority over autologous cartilage implantation. Collectively, these findings identify differentiation stage as an intrinsic bioassembly variable and establish a stage-programmed strategy for constructing hierarchical cartilage grafts. Both BM-MSCs and UC-MSCs supported stage-defined assembly in vitro, warranting further evaluation of UC-MSCs as a potential allogeneic cell source in adequately powered studies.
Retinoic acid receptor α (RARα) is a promising yet challenging target in treating colorectal cancer (CRC). Traditional RARα-binding modulators often fail to fully inhibit downstream oncogenic pathways and cannot eliminate the pre-existing RARα protein, frequently resulting in drug resistance and treatment failure. To overcome these limitations, we designed a series of proteolysis-targeting chimeras (PROTACs) based on the ligand CA77.1, which are bifunctional molecules that recruit the ubiquitin–proteasome system for RARα degradation.Among these candidates, compound Z1 proved the most potent degrader, demonstrating a DC50 of 6.02 ± 1.05 μM and effective suppression of CRC cell proliferation and migration. Considering the generally poor solubility and membrane permeability of PROTACs, we encapsulated Z1 within Polygonatum sibiricum exosome-like nanoparticles (PsELNs). Compared with free Z1, the Z1/PsELNs delivery system enhanced RARα degradation in vitro by 2.2-fold and improved in vivo antitumor efficacy by 1.8-fold, while also promoting tumor targeting and overall bioavailability. These findings provide a feasible strategy for degrading RARα in CRC and highlight the potential of plant-derived exosome-like nanoparticles as efficient carriers for PROTAC delivery, indicating a new direction for targeted cancer therapy.
Gastrointestinal stenosis following endoscopic intervention remains a major clinical challenge, largely driven by excessive fibrotic remodeling rather than persistent inflammation alone. Although glucocorticoids are widely used to suppress acute inflammatory responses, their therapeutic benefit is limited since the core profibrotic circuitry governed by the TGF-β/Smad signaling pathway. In fibrotic lesions throughout the gastrointestinal tract, activated myofibroblasts and dense extracellular matrix deposition increase tissue stiffness, reinforce mechanotransduction-dependent TGF-β activation, and restrict effective intralesional drug retention, thereby establishing a self-sustaining profibrotic microenvironment. To address this mechanistic barrier, we developed an octopus-inspired suction-cup microneedle patch with a mechanically decoupled architecture composed of rigid PLGA microneedles (MN) and a flexible pectin-based substrate. This design enables efficient penetration into stiffened mucosa and stable adhesion within the moist, dynamic luminal environment. The system achieves localized co-delivery of Budesonide (BUD) and SMAD7, an endogenous intracellular antagonist of TGF-β/Smad signaling. Comprehensive in vitro mechanistic studies and in vivo wound-healing models demonstrate effective intralesional retention, significant suppression of fibrotic remodeling, and promotion of mucosal regeneration. By simultaneously targeting inflammation and the core fibrotic signaling cascade, this bioinspired microneedle platform offers a mechanistically informed and clinically translatable strategy for the prevention and treatment of post-endoscopic gastrointestinal stenosis.
Understanding the mechanisms governing cancer cell migration is essential for elucidating the early events of colorectal cancer metastasis. Here, we report the development of a light-tunable three-dimensional (3D) bioprinted tumour-on-chip platform for monitoring the migration of colorectal cancer cells under biomimetic microenvironmental conditions. The platform integrates digital light processing (DLP)-based 3D bioprinting with microfluidic technology to recreate structural and mechanical features of the colorectal tumour microenvironment. A hybrid bioink composed of gelatin methacryloyl (GelMA), Matrigel, and type I collagen was formulated to balance DLP printability with biologically relevant extracellular matrix components. Multi-compartment tumour constructs were fabricated with HCT116 colorectal cancer cells spatially confined within a central tumour region, while human umbilical vein endothelial cells (HUVECs) were incorporated into surrounding compartments under co-culture conditions. By modulating the projected light intensity, constructs with tunable properties were generated to investigate the influence of matrix mechanics and transport on cancer cell behaviour. Comparison of Day 1 and Day 4 fluorescence images revealed outward redistribution of the HCT116-positive signal beyond the initially printed tumour core, consistent with colorectal cancer cell migration. The extent of this redistribution was influenced by the light-defined matrix properties and the presence of the neighbouring HUVEC-containing co-culture compartment, highlighting the combined role of physicochemical and cellular cues in regulating tumour cell behaviour. The system also establishes a foundation for future studies of tumour invasion, endothelial barrier interactions, and therapeutic screening under controlled perfusion conditions, supporting the advancement of personalized cancer models and anti-metastatic drug development.
Radiation-induced oral mucositis (RIOM) is the most common complication in patients receiving radiotherapy for head and neck, to which ferroptosis is an important contributor. Transferrin receptor (TFRC) -mediated endocytosis is a critical source of iron. Accordingly, we proposed that inhibiting ferroptosis by disrupting TFRC mediated-iron uptake. In this study, we developed endosome-targeting self-assembling nanoparticles (CB NPs) integrated into a detachable microneedle patch (CBT@MNs) for precise and synergistic RIOM therapy. This system integrated the clinically conventional drugs chloroquine and baicalin and loaded into MN patch for mucosal drug delivery. In the tongue mucosa, the MN tips released CB NPs. Upon entering endosomes through the endocytosis pathway, CB NPs disrupted endosomal acidification through the proton sponge effect, which may block TFRC recycling, achieving long-term inhibition of ferroptosis and inflammation efficacy. In rat models of RIOM, CBT@MNs dramatically attenuated mucosal ulceration and accelerated healing via anti-inflammation, angiogenesis, and collagen deposition. Transcriptomic analysis further revealed that CBT@MNs suppressed ferroptosis and inflammatory signaling. This radioprotective strategy for inhibiting ferroptosis and regulating redox homeostasis provided a novel approach for designing tissue engineering materials.
To tackle the global cardiovascular disease epidemic, vascular cell culture requires scalable, efficient, and reproducible methods for differentiating cells. However, no studies have validated whether automation, essential for scale-up, preserves differentiation quality of cells. Here, we developed a differentiation protocol for induced pluripotent stem cell (iPSC)-derived vascular smooth muscle cells (iVSMCs) that is applicable to both manual, and automated robotic culture. iPSC lines generated from male and female donors across various ages were used to optimize the generation of iVSMCs. iVSMCs had consistent morphology and protein expression, which were largely similar to those of primary VSMCs, including expression of myosin heavy chain-11 (MYH11), α-smooth muscle actin (α-SMA), transgelin (TAGLN) and calponin (CNN1). Functionally, these iVSMCs responded to the vasoconstrictor carbachol. Coupling this protocol with an automated Hamilton liquid-handling robotics system allowed the generation of iVSMCs in large quantities, that were morphologically similar to manually differentiated iVSMCs. Comparative proteomic analysis confirmed that protein expression was substantially the same between automated and manual differentiation methods. Automation markedly reduced manual labor and facilitated increased production without sacrificing cell quality. This study demonstrates the feasibility of automating iVSMC differentiation, marking a significant step towards scalable VSMC manufacture for three-dimensional applications, and for the ever-growing demands of organoid and tissue engineering applications.
Hepatocellular carcinoma (HCC) presents significant therapeutic challenges due to enhanced liver cancer stem cell (LCSC) stemness and sorafenib resistance after radiofrequency ablation (RFA). To address these limitations, biohybrid nanovesicles (hNVs) are prepared by fusing milk-derived exosomes with sorafenib-resistant LM3 cell membranes as nanovectors for targeted delivery of the HSP90 inhibitor alvespimycin (17-DMAG). The hNVs exhibit enhances tumor-homing capability through homologous targeting, achieving 3.2-fold higher tumor accumulation compared to unmodified exosomes. RFA of HCC significantly upregulates the expression of HSP90, leading to enhanced LCSC stemness and sorafenib resistance. In vitro and in vivo studies demonstrate that 17-DMAG loaded hNVs (17-DMAG@hNVs) effectively suppress LCSC stemness by downregulating HSP90 and its downstream signal pathways (TGF-β/Smad3 and JAK/STAT3), thereby restoring sorafenib sensitivity. Therefore, 17-DMAG@hNVs remarkably enhance the therapeutic efficacy of sorafenib after RFA of HCC. The reversal of LCSC stemness by inhibiting HSP90 expression using 17-DMAG@hNVs provides a promising approach to overcome sorafenib resistance for enhanced therapy of HCC after RFA.
Optogenetics provides exceptional spatial, temporal, and cell-type specificity for manipulating biological function, but the ability to produce a light-evoked response does not by itself establish therapeutic relevance. Disease-oriented studies now span molecular assembly, neuronal excitability, neuromuscular transmission, circuit modulation, engineered human tissues, closed-loop control, and early human intervention, yet these outcomes support fundamentally different levels of inference. Here, we critically examine optogenetic applications across neuromuscular and neurological disorders and propose an evidence-tiered framework for distinguishing mechanistic causality, disease-relevant functional validation, in vivo therapeutic modulation, integrated translational system validation, and human clinical proof-of-concept. Neuromuscular disorders illustrate how optogenetics can connect molecular mechanisms and activity-dependent phenotypes to human motor-unit function, whereas studies in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, stroke, and epilepsy primarily define causal pathways, network states, stimulation rules, and opportunities for clinically feasible neuromodulation. Human-derived motor-unit systems, organoids, and other bioengineered platforms provide important functional de-risking but should not be equated with clinical evidence. Retinal optogenetics currently provides the clearest human proof-of-concept, while its favorable anatomy limits generalization to deeper or distributed neural targets. We further show that translational progression depends on coordinated optimization of gene delivery, actuator performance, optical dosimetry, material–tissue compatibility, implant mechanics, sensing and feedback control, durability, safety, and clinically meaningful advantage over established therapies. Accordingly, optogenetic translation should be viewed as a coupled gene–material–device–control problem rather than as optical stimulation alone. This framework clarifies what different experimental designs demonstrate, where evidence remains incomplete, and which biological and engineering barriers must be resolved before optical specificity can be converted into durable clinical benefit.
The excessive reactive oxygen species (ROS) play an important role in the occurrence and progression of Parkinson’s disease (PD). To investigate whether the antioxidant enzymes can scavenge the ROS level in vivo and treat PD efficiently, superoxide dismutase (SOD) was encapsulated into HEK293-derived exosomes to prepare SOD-loaded exosomes (SOD@EXO), and catalase (CAT)-like cerium oxide nanozyme (CeO2) was mixed with SOD@EXO to construct the formulation, namely SOD@EXO+CeO2. The formulation with cup-shaped morphology showed high SOD and CAT activities, which could scavenge the ROS level in a cascade manner. In vitro neuroprotective trials against SH-SY5Y cells revealed that SOD@EXO+CeO2 could efficiently prevent the neurotoxicity in 1-methyl-4-phenylpyridine-induced PD cell model. Moreover, the exosomes could be significantly accumulated in brain after the intranasal administration in comparison to the intravenous injection. Finally, the system was found to ameliorate the behavior disorder and relieve the inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice model after the intranasal administration of SOD@EXO+CeO2. In a word, SOD@EXO+CeO2 could act in a cascade manner to scavege ROS, relieve the inflammatory response and improve the behavior disorder. Our results provide a new paradigm to construct the prevention and treatment strategy of dyskinesia diseases in central nervous system in future.
Atrial fibrillation (AF)-associated fibrosis is a heterogeneous component of atrial cardiomyopathy that contributes to conduction slowing, anisotropy, reentry susceptibility, and reduced therapeutic responsiveness. However, translation of anti-fibrotic strategies remains limited by the biological heterogeneity of AF and by models that incompletely reproduce human atrial cell composition, mechanics, perfusion, and electrophysiology. This narrative review critically evaluates the convergence of patient-specific induced pluripotent stem cell (iPSC) models, biomimetic atrial-on-a-chip platforms, and nanomedicine. We distinguish direct atrial or AF-specific evidence from cardiac but non-atrial studies and from engineering principles extrapolated from extracardiac fibrosis or oncology. Direct evidence supports chamber-validated iPSC-derived atrial cardiomyocytes, structured cardiomyocyte-fibroblast cocultures, and selected chamber-specific vascularized atrial microtissues for interrogating electrical and fibrotic phenotypes. In contrast, fully integrated patient-specific systems that combine chamber-specific cells, vascular perfusion, controlled mechanical loading, immune components, multiparametric functional readouts, and nanomedicine testing remain at an early stage. We therefore position atrial-on-a-chip platforms as fit-for-purpose, high-content experimental systems for mechanistic comparison and candidate prioritization, rather than as established substitutes for in vivo physiology or clinical trials. Nanocarrier design may address delivery barriers involving biodistribution, dense extracellular matrix, cellular uptake, and endosomal escape; nevertheless, most supporting evidence is currently cardiac non-atrial or extracardiac, and atrial selectivity requires direct validation. By linking evidence level, model capability, assay quality control, delivery performance, and functional safety, this review proposes a staged framework for investigating AF-associated fibrosis and for defining the experiments required before clinical translation.
Dendritic cell (DC)-based immunotherapy shows limited efficacy against hepatic fibrosis, and the underlying mechanometabolic crosstalk remains unclear. Here, from a mechanobiological perspective, we demonstrate that increased extracellular matrix (ECM) stiffness in fibrotic liver triggered antigen-independent abnormal DC maturation, characterized by elevated co-stimulatory molecules, impaired phagocytic capacity, reduced IL-10 secretion, and suppressed regulatory T cell (Treg) differentiation. Mechanistically, stiff ECM inhibited the AMPK-LXRα-ABCG1 signaling axis in DCs, reducing cholesterol efflux and promoting intracellular cholesterol accumulation. Cholesterol depletion or AMPK activation reversed stiffness-induced abnormal DC maturation. In mouse models, combined treatment with pirfenidone and simvastatin reduced liver stiffness, collagen deposition, and restored immune tolerance by correcting DC cholesterol metabolism. Our study identified a mechanometabolic pathway linking matrix stiffness to DC dysfunction, providing a promising immunometabolic strategy for antifibrotic therapy.
Acute orchitis and other inflammatory testicular diseases lack delivery platforms that enable label-free fluorescence tracking of drug distribution in inflamed testes. Here, we show that three clinically approved leukotriene receptor antagonists, namely Pranlukast, Zafirlukast, and Montelukast can be transformed into self-reporting, self-delivering, and self-therapeutic nanotheranostics. These drugs intrinsically possess aggregation-induced emission (AIE): extensive intermolecular halogen and hydrogen bonds simultaneously restrict intramolecular motion to generate bright solid-state fluorescence and drive spontaneous self-assembly into uniform, PEG-stabilized nanocrystals. Unlike conventional dye-labeled nanocarriers, in which dye leakage causes false signals, AIE fluorescence faithfully reports the aggregated nanocrystal state, enabling monitoring of drug integrity. Beyond their canonical anti-leukotriene activity, these drugs directly suppress NF-κB signaling and scavenge reactive oxygen species—mechanisms highly relevant to acute orchitis pathogenesis, which involves TLR4/MyD88/NF-κB activation and oxidative stress. In LPS-stimulated cells, the nanocrystals suppress NF-κB activation and scavenge reactive oxygen species. In a rat model of acute orchitis, AIE imaging reveals efficient testicular accumulation, which correlates with attenuated histopathological damage, restored oxidative stress balance, and downregulation of the TLR4/MyD88/NF-κB and PK2/PKR1 pathways, with no obvious adverse effects on the measured short-term reproductive indices (sperm morphology and testosterone levels) observed within the experimental timeframe. This strategy converts old drugs into minimal-excipient, self-monitoring AIE nanotheranostics for imaging-guided orchitis therapy.
Background The progression of atherosclerosis is driven by the continuous accumulation of macrophage foam cells and their subsequent demise via ferroptosis—an iron-dependent, lipid peroxidation-driven form of cell death that expands the necrotic core. However, the clinical translation of anti-ferroptotic agents is severely hindered by poor localization to the vascular intima and rapid systemic clearance. Here, we engineered macrophage-biomimetic nanoparticles loaded with curcumin (Cum@MM-NPs) to actively target vulnerable plaques, halt localized ferroptosis, and systemically reprogram lipid metabolism. Methods Polymeric poly(lactic-co-glycolic acid) cores loaded with curcumin were cloaked with RAW264.7 macrophage-derived cell membranes via co-extrusion. in vitro cellular targeting, lipid handling, and anti-ferroptotic mechanisms were evaluated using oxidized LDL (ox-LDL)-stimulated macrophages. in vivo pharmacokinetic stability, homotypic plaque targeting, and therapeutic efficacy were comprehensively assessed in high-fat diet (HFD)-fed ApoE-/- mice. Furthermore, untargeted serum lipidomics were utilized to evaluate systemic metabolic reprogramming. Results Cum@MM-NPs exhibited a definitive core-shell architecture, successfully retained characteristic macrophage surface antigens, and demonstrated sustained curcumin release. in vitro, the biomimetic coating facilitated homotypic targeting to foam cells while rescuing them from ox-LDL-induced ferroptosis by chelating labile iron (Fe2+), restoring GPX4 antioxidant defenses, and preventing pathological lipid droplet accumulation. in vivo, Cum@MM-NPs exhibited prolonged circulation and highly specific accumulation in aortic plaques. Therapeutically, Cum@MM-NP administration drastically reduced aortic plaque burden, inhibited local pro-inflammatory cytokine secretion, and stabilized vulnerable lesions by enhancing collagen-rich fibrous caps. Mechanistically, Cum@MM-NPs successfully arrested intraplaque ferroptosis, evidenced by normalized mitochondrial ultrastructure and cleared lipid peroxides (4-HNE). Beyond localized plaque stabilization, untargeted lipidomics revealed that the nanotherapy comprehensively reversed HFD-induced hepatic steatosis and systemically depleted circulating pro-ferroptotic polyunsaturated phosphatidylethanolamines (PE-PUFAs). Conclusions Cum@MM-NPs function as a highly biocompatible, dual-action nanotherapeutic platform. By simultaneously quenching localized vascular ferroptosis and systematically dismantling the pro-ferroptotic lipidome, this macrophage-biomimetic strategy offers a highly translatable paradigm for the treatment of advanced atherosclerosis and interconnected metabolic comorbidities.
