This study presents a nanotherapeutic strategy for diabetic peripheral neuropathy (DPN) by developing polyimide-coated zeolitic imidazolate framework-8 core-shell nanovesicles loaded with interleukin-2 (MOF@PI-IL2) for inflammation-microenvironment-responsive delivery of IL-2 and relatively preferential activation of regulatory T cells (Treg cells). Given that DPN is characterized by chronic neuroinflammation and immune dysregulation with impaired Treg cell numbers and activity, the engineered nanoparticles promote Treg cell expansion and immunometabolic reprogramming while suppressing CD8+ T cell cytotoxicity. Through comprehensive evaluation using multiomics integration, biomineralization synthesis, inflammatory models, and DPN mouse experiments, the system demonstrated favorable physicochemical properties and biodistribution. Treatment with MOF@PI-IL2 significantly improved both electrophysiological parameters and structural nerve function. Forkhead box P3 knockdown experiments confirmed that the therapeutic effects were Treg cell dependent. Multiomics analysis further suggested that the treatment partly corrected short-chain fatty acid and tryptophan metabolic dysregulation and was associated with reconstruction of correlations within a "metabolism-IL-2 response-Treg cell module". This work provides an inflammation-microenvironment-responsive and translatable Treg-cell-targeted nanoimmunotherapeutic strategy for DPN while broadening the conceptual framework for treating chronic inflammatory diseases through immunometabolic modulation.
The female reproductive tract (FRT) is an intricate and highly regulated network comprising the ovaries, fallopian tubes, uterus, cervix, and placenta, which work in concert to govern complex reproductive functions. Dysfunction within any of these organs can lead to serious pathological conditions, including infertility, pregnancy complications, and gynecological cancers. Although conventional 2-dimensional (2D) cultures and animal models have provided foundational insights, they are limited in their ability to recapitulate human-specific 3D tissue architecture and dynamic biochemical microenvironments. To address these limitations, organoid and organ-on-a-chip (OoC) technologies have emerged as a powerful 3D biomimetic platform. Organoids preserve epithelial identity, cellular heterogeneity, and patient-specific phenotypes, whereas OoC systems incorporate microfluidic flow, mechanical stimulation, and multicompartmental interfaces to model organ-level physiology. This review provides an organ-specific overview of recent advances in organoid and OoC systems across the FRT, discusses their advantages and current limitations relative to traditional models, and highlights their potential to transform reproductive biology research, disease modeling, and translational applications.
Biomedical membranes are among the most widely used biomaterials in clinical regenerative medicine due to their ease of application, biocompatibility, and versatility across multiple tissues. However, conventional membranes have been limited to passive roles serving as physical barriers or wound coverings without an intrinsic capability to initiate or orchestrate true tissue regeneration. Here, we report the design, development, and clinical validation of an active tissue-regenerative biomedical membrane patch, aiming to advance biomedical membranes from passive protection toward active human tissue regeneration. In this study, we developed a multifunctional, collagen-coated polylactic-co-glycolic acid nanotopographical scaffold (Col-NS) that mimics the native extracellular matrix to enhance soft- and hard-tissue regeneration. In a clinical trial for laser-induced human skin injury, Col-NS substantially improved healing outcomes, achieving accelerated wound contraction, dermal volume restoration, reduced surface roughness, and decreased transepidermal water loss relative to standard care. In human dental procedures, including alveolar ridge preservation and guided bone regeneration, Col-NS enabled robust bone formation, stable implant osseointegration, and complication-free recovery. These findings demonstrate the translational feasibility of an extracellular-matrix-mimetic nanoengineered scaffold across soft- and hard-tissue applications and support its potential as a clinically relevant platform for regenerative medicine. This work may contribute to broadening the clinical role of biomedical patches from passive coverings toward active regenerative platforms.
Diabetic wounds are characterized by oxidative stress, chronic inflammation, and impaired tissue regeneration under persistent hyperglycemic conditions. Herein, we report an injectable dual-dynamic covalent hydrogel fabricated from phenylboronic-acid-functionalized oxidized sodium alginate and gallic-acid-conjugated chitosan. Crosslinked via reversible Schiff base and boronate ester bonds, the hydrogel exhibits excellent injectability, self-healing capability, and structural stability. Under hyperglycemic conditions, competitive glucose binding modulates the boronate ester equilibrium and induces glucose-responsive release of galloyl-containing species. These glucose-responsive release behaviors contribute to the antioxidant, antibacterial, and immunoregulatory activities of the hydrogel. In vitro and in vivo results demonstrate that the hydrogel promotes macrophage polarization toward the anti-inflammatory M2 phenotype, alleviates inflammatory responses, enhances angiogenesis, and accelerates skin regeneration. Collectively, the phenylboronic-acid-functionalized oxidized sodium alginate and gallic-acid-conjugated chitosan hydrogel represents a multifunctional glucose-responsive biomaterial with considerable potential for diabetic wound therapy.
Electric field-based therapies are rapidly emerging as innovative modalities in the fight against cancer, offering targeted, minimally invasive, and often immunomodulatory alternatives to conventional treatments. This review comprehensively examines the current landscape and prospects of electricity-based locoregional cancer therapies and their associated drug delivery technologies. Key modalities, including irreversible electroporation, tumor-treating fields, radiofrequency ablation, electrochemotherapy, and iontophoresis, are discussed regarding their mechanisms of action, clinical applications, and integration with immunotherapy. In addition, emerging strategies such as smart electro-responsive drug carriers and integrative therapeutic systems are highlighted as promising approaches for achieving electrically controlled, site-specific, and precision-guided drug delivery. Although electricity-based locoregional cancer therapies show promise, challenges such as variable tissue responses, device optimization, and long-term safety remain. Current research aims to address these issues and enhance outcomes through combinations with immunotherapy. By drawing on advances in bioelectricity, nanotechnology, and immunology, these therapies have the potential to substantially improve the precision and personalization of cancer treatment.
Spinal cord injury (SCI) triggers an excessive inflammatory response, characterized by the up-regulation of various inflammatory factors that impede neural regeneration and functional recovery. Interleukin-6 (IL-6) is an early and critical inflammatory mediator observed in lesions post-SCI. Antagonizing the signaling pathway presents a promising strategy to mitigate early inflammation and secondary injury after trauma. Here, we identified specific activation of the IL-6 receptor in neurons and microglia in lesions, indicating their responsiveness to early up-regulated IL-6 signaling within the microenvironment. In vitro, neutralizing IL-6 signaling in microglia effectively alleviated their inhibitory effects on neuronal axon growth in conditioned media. Building on this, we developed a reactive-oxygen-species-responsive hydrogel for the sustained local delivery of tocilizumab, an IL-6 receptor antagonist, and implanted it in a complete transection SCI model. In vivo, sustained IL-6 receptor blockade effectively reduced early inflammatory cell infiltration, modulated microglial polarization toward an anti-inflammatory phenotype, and fostered neuronal regeneration within the lesion. Importantly, this therapeutic intervention promoted long-term hind limb functional recovery in SCI mice. This study underscores the therapeutic potential of precisely targeting early inflammatory cytokine signaling pathways, particularly IL-6, to improve outcomes after SCI.
Lung cancer remains a leading cause of cancer-related mortality worldwide, with therapeutic outcomes frequently constrained by drug resistance, tumor heterogeneity, and systemic toxicity. Multimodal synergistic therapy has emerged as a promising strategy to address these challenges. In this study, we developed a biodegradable nanosystem, designated CSZG, which integrates glucose oxidase (GOx) and copper-rich copper selenide (Cu2-x Se) within a ZIF-8 nanocarrier for lung cancer therapy. CSZG exhibited pH-responsive GOx release, favorable colloidal stability, and retained glucose-responsive catalytic activity of GOx. GOx supplied hydrogen peroxide (H2O2) through glucose oxidation, while Cu+ catalyzed the conversion of H2O2 into cytotoxic hydroxyl radicals (•OH) under near-infrared (NIR) irradiation, thereby enhancing chemodynamic therapy. Electron spin resonance analysis directly confirmed NIR-enhanced •OH generation, particularly under acidic conditions. In addition, CSZG + NIR induced copper-dependent mitochondrial dysfunction with cuproptosis-associated features, as evidenced by aggregation of dihydrolipoamide S-acetyltransferase, down-regulation of ferredoxin 1 , depletion of Fe-S cluster proteins, and partial reversal by tetrathiomolybdate. The Cu2-x Se-containing platform also promoted macrophage polarization toward an M1-like phenotype. In vivo, CSZG + NIR achieved a tumor inhibition rate of 91.7% and demonstrated favorable short-term systemic biosafety under the tested therapeutic conditions. Collectively, these findings highlight CSZG as a promising multimodal therapeutic platform for lung cancer.
Osteoarthritis (OA) is a complex pathological condition characterized by oxidative stress and progressive cartilage breakdown. The reciprocal relationship between the inflammatory joint milieu and impaired chondrocyte function drives the progressive deterioration of OA. Inspired by natural metalloenzymes that utilize metal ions as catalytic centers, stable metal-organic frameworks (MOFs) assembled from natural polyphenols and metal ions have emerged as promising candidates for mitigating inflammatory diseases. Nonetheless, numerous nanozymes are limited to restricted antioxidant capacity, failing to eliminate various kinds of reactive oxygen species (ROS). To address these limitations, we engineered the MnO2@UiO-66(Ce) (abbreviated as MCU) system, which was fabricated through the integration of MnO2 into nanoscale mesoporous UiO-66 MOFs for OA therapy. Within the MOF architecture, MnO2 coupled with Ce clusters establishes a continuous superoxide dismutase/catalase cascade reaction platform that enables efficient ROS scavenging. In vitro and in vivo experiments reveal that the MCU system significantly reduces intracellular ROS accumulation and ameliorates the inflammatory microenvironment, consequently attenuating cartilage matrix destruction. Further mechanistic investigations indicates that MCU alleviates OA progression through the epigenetic activation of Wnt/β-catenin via adenosine monophosphate-activated protein kinase-disruptor of telomeric silencing 1-like-mediated H3K79 methylation. In summary, this study suggests that this highly efficient cascade catalytic system may represent a promising strategic avenue for combating oxidative stress in chronic inflammatory diseases.
Effective bone regeneration requires biomaterials that exhibit appropriate bioactive functions, particularly osteoconductive and osteoinductive properties. Here, we engineered a cell-derived, decellularized extracellular matrix (cdECM) into a novel mineralized ECM scaffold by harnessing the polymer-induced liquid precursor (PILP) process, an effective strategy for generating calcium phosphate (CaP) mineralized constructs. Mineral deposition within cdECM was successfully achieved through the PILP mineralization, which stabilizes the amorphous precursor phase and promotes matrix-associated mineralization. The resulting mineralized ECM (mECM) exhibited osteoconductive properties, as evidenced by excellent cytocompatibility and enhanced cell proliferation of osteogenic cells. The mECM also demonstrated osteoinductive potential, as confirmed by enhanced alkaline phosphatase activity, increased calcification, and up-regulated osteogenic gene expression in mouse preosteoblasts and human mesenchymal stem cells. Moreover, mECM promoted M2-like macrophage polarization and enhanced tubular formation of endothelial cells. To enable localized in vivo delivery of both ECM-derived biological cues and minerals, a sheet-type mECM scaffold was fabricated using hyaluronic acid as a supporting matrix and further stabilized by glutaraldehyde vapor crosslinking. In a mouse calvarial defect model, the mECM sheet facilitated new bone formation and supported advanced bone maturation, accompanied by enhanced angiogenesis and an M2-dominant anti-inflammatory milieu at an early time point. Collectively, our findings demonstrate that PILP mineralization can be successfully applied to cdECM for generating a bioactive mECM scaffold with enhanced regenerative capacity, representing a promising biomaterial platform for bone tissue regeneration.
Biogenic hydroxyapatite (BHA) is widely used for oral bone defect regeneration, yet its osteogenic efficacy is limited by slow osteogenesis and insufficient bone volume, which may be attributed to early inflammatory responses. The investigation of granular biomaterials is further challenged by conventional in vitro models that fail to ensure adequate cell-material interactions and efficient RNA extraction, limiting experimental reliability. Here, we developed an improved direct coculture system together with an optimized RNA extraction strategy to address these limitations. Using this platform, we characterized BHA-induced inflammatory responses at the gene, protein, and transcriptomic levels. Our results showed that the inflammatory activity of BHA is associated with its calcium-enriched surface, which activates the Toll-like receptor 4 signaling pathway. Furthermore, a calcium pre-adsorption strategy was introduced to modulate surface ion activity, which reduced calcium enrichment and attenuated inflammatory signaling. These findings suggest that modulating calcium enrichment capacity may offer a promising strategy to regulate the immune response of hydroxyapatite-based bone substitutes and improve their biological performance.
Balancing short-term antibacterial needs with long-term anti-inflammatory effects remains a major challenge in wound healing. Multifunctional bioactive materials capable of both efficient antibacterial action and inflammation modulation represent a promising solution. However, the majority of traditional antibacterial biomaterials possess only a single antibacterial effect, and their synthesis and preparation are intricate, which might restrict their clinical transformation. Chlorogenic acid is a natural compound endowed with anti-inflammatory properties. However, it is beset by certain inherent drawbacks, including poor water solubility and limited bioavailability. To overcome these difficulties, we have fabricated multifunctional nanoparticles (chlorogenic acid-iron nanoparticles, CA-Fe NPs) through the co-assembly of chlorogenic acid and iron ions in a straightforward manner. We found that CA-Fe NPs exhibit excellent photothermal conversion performance in vitro. Upon near-infrared (NIR) irradiation, they exhibit potent broad-spectrum antimicrobial activity against Staphylococcus aureus, Escherichia coli, Candida albicans, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The CA-Fe NPs markedly reduced H2O2-induced reactive oxygen species levels and apoptosis in epithelial cells and suppressed lipopolysaccharide-induced M1 macrophage polarization in RAW 264.7 cells. Transmission electron microscopy results revealed enhanced bacterial membrane disruption by CA-Fe NPs under NIR irradiation, causing pronounced protein leakage. Transcriptomic analysis indicates that CA-Fe NPs combined with NIR disrupt the tricarboxylic acid cycle, cell-wall organization, and other metabolic processes. In vivo, within a methicillin-resistant Staphylococcus aureus-infected skin wound model, CA-Fe NPs maintained photothermal efficacy, effectively reduced serum levels of interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha, and accelerated wound healing. These findings suggest that CA-Fe NPs are multifunctional materials with broad-spectrum bactericidal ability, antioxidant, anti-inflammatory, and wound-healing-promotion properties. These nanoparticles possess promising prospects for biomedical applications.
The global cosmetic surgery industry is actively seeking alternatives that can overcome the limitations of traditional animal-derived exosomes, which face clinical translation bottlenecks including high costs, immunological risks, and zoonotic disease hazards. Plant-derived exosomes (PLDEs) offer a promising attractive "green" nanotechnology platform owing to their inherent safety, minimal immunogenicity, and suitability for scalable manufacturing. Their core advantage lies in delivering plant-specific bioactive compounds (such as small RNAs and secondary metabolites) that target multiple key signaling pathways, including skin aging, pigmentation, inflammation, and regeneration, through cross-species regulatory mechanisms. This review critically synthesizes PLDE biological basis, isolation methods, and evidence for antiaging, skin brightening, and regenerative efficacy. It delineates how surface functionalization, targeted drug delivery, and biomaterial integration (hydrogels and microneedles) optimize PLDE targeting. Finally, it addresses current challenges in clinical translation and standardization, offering a forward-looking perspective on the development of next-generation PLDE-based therapies for minimally invasive aesthetic applications.
Diabetic kidney disease (DKD) is identified as the major contributor to the development of end-stage renal disease, with its clinical incidence increasing. Emerging studies link DKD closely to renal lipid deposition, tubular injury, and glomerulosclerosis-pathological processes driven by renal lipid metabolism disorders that ultimately induce renal fibrosis. However, targeted therapeutics for renal lipid deposition are scarce. This study fills this research gap: first, clinical database analyses identified a positive correlation between up-regulated rho-associated coiled-coil protein kinase 1 (ROCK1) expression in renal tubules and progressive renal function deterioration in DKD patients, a finding recapitulated in DKD mouse models, which also exhibited renal tubular ROCK1 up-regulation and concomitant lipid accumulation; second, molecular docking, surface plasmon resonance, and cellular thermal shift assay confirm that the natural molecule stigmasterol (ST) binds to ROCK1 and inhibits its expression with a dose-dependent trend; and, third, in vivo and in vitro experiments demonstrate that ST alleviates lipid accumulation, mitochondrial damage, and renal fibrosis in DKD via the ROCK1/p38 mitogen-activated protein kinase/peroxisome proliferator-activated receptor α axis. In conclusion, ST exerts direct renoprotective effects by regulating the ROCK1 pathway to improve renal lipid metabolism, reduce mitochondrial damage, and inhibit fibrosis, highlighting its potential as a novel ROCK1 inhibitor. This study identifies ST as a candidate for targeted intervention in DKD-related lipid metabolism, validates ROCK1 as a therapeutic target, provides an experimental basis for the DKD treatment strategy of "targeting ROCK1 to synergistically improve lipid metabolism and mitochondrial function", and opens new avenues for natural products in metabolism-related nephropathies.
Inflammatory bone loss represents a major clinical challenge, leading to irreversible tissue damage and impaired function. Probiotic-derived nanovesicles show immense potential as novel cell-free nanomedicines; however, the lack of clarity regarding their precise mechanism of action in bone tissue regeneration restricts their clinical application. This study utilized a ligature-induced periodontitis mouse model (in vivo) and in vitro models, including macrophage functional assays and macrophage-osteoblast co-culture systems, to investigate the therapeutic effects and mechanism of Lactobacillus rhamnosus GG-derived extracellular vesicles (LEVs). In the periodontitis mouse model, LEVs effectively mitigated inflammatory infiltration and promoted alveolar bone regeneration. In vitro studies demonstrated that LEVs enhance macrophage polarization toward a reparative (M2) phenotype. Mechanistically, we identify LEVs as bioactive nanocarriers that deliver tryptophan metabolites. Upon internalization by macrophages, these metabolites trigger a critical metabolic and phenotypic shift by activating the aryl hydrocarbon receptor (AhR). Further research revealed that this effect is mediated by the AhR/NAD(P)H:quinone oxidoreductase 1 (NQO1)/carnitine palmitoyltransferase 1A (CPT1A) signaling axis: AhR transcriptionally up-regulates NQO1, which critically inhibits the 26S proteasome-mediated degradation of CPT1A. The resulting sustained CPT1A expression dramatically boosts fatty acid oxidation, which is essential for driving the reparative macrophage phenotype. These findings highlight the critical role and molecular delivery mechanisms of probiotic-derived nanovesicles in ameliorating inflammatory bone loss via immunometabolic reprogramming, thereby providing new targets and a theoretical basis for their application as nanocarriers in regenerative biomaterials.
Aberrant glycosylation is a well-known pathological alteration that accompanies tumor onset, progression, and eventual metastasis. For colorectal cancers, there is strong evidence to show that glycans containing α2,3-sialic acid, α2,6-sialic acid, and fucose are frequently up-regulated. In this work, we report the application of lectin-directed protein aggregation therapy (LPAT) to target hypersialylated and hyperfucosylated colorectal cancer cells. This system relies on the concept of cancer-activated lectin multivalency, where tumor-associated proteases can elicit the self-assembly of multivalent lectin complexes that can selectively impair the metastatic activities of cancer cells. After screening LPAT agents against a panel of 5 colorectal cancer cell lines, the most effective targeting was identified against the hyperfucosylated/matrix metalloproteinase-9-overexpressing HCT-116 cell line, which showed significant reductions in invasion and migration upon treatment. Experiments then showed that hyperfucosylation targeting could be used as a viable approach to prevent liver and kidney tumor development in a metastatic colorectal mouse model. Overall, this work highlights the viability of using LPAT to discriminate the aberrant glycosylation of highly metastatic colorectal cancer cells as a means to prevent their onset and progression.
Photodynamic therapy is traditionally based on reactive-oxygen-species-mediated tumor cell killing, but its immunomodulatory capacity is not fully explored. Plant-derived exosome-like nanovesicles provide a natural photosensitizer platform with potential for dual tumoricidal and immune-modulating effects. This study investigated whether light activation of Hypericum perforatum-derived exosome nanovesicles (HPDENs) remodels their microRNA cargo to enhance antitumor activity and reprogram the tumor immune microenvironment. Photoactivation significantly up-regulated miR-172f-p3 in HPDENs, which directly targeted CD24 messenger RNA and suppressed its expression in MCF-7 cells. CD24 down-regulation reprogrammed co-cultured M2 macrophages toward an M1 phenotype by attenuating the CD24-Siglec-G/10 axis. In vivo, light-treated HPDENs and miR-172f-p3 mimics inhibited tumor growth, promoted M1 polarization, and displayed excellent safety with no observable systemic toxicity. Photoactivated HPDENs exert dual antitumor effects by inducing direct tumor suppression and remodeling the immune microenvironment through miR-172f-p3/CD24-Siglec-G/10 signaling. This strategy offers a novel immunotherapeutic avenue that synergizes with photodynamic therapy, supporting the development of plant-derived nanovesicles as next-generation cancer therapeutics.
Atopic dermatitis is a chronic inflammatory skin disease characterized by dry skin, itching, and recurrent eczematous lesions. Although current therapeutic strategies are effective, their use is often limited due to adverse effects. Therefore, the development of safer and more effective alternatives is required. Tryptanthrin is a yellow-gold alkaloid compound with anti-atopic and various pharmacological activities. However, its poor aqueous solubility results in low topical bioavailability. A tryptanthrin-loaded liposomal lotion was developed using a design of experiments approach to improve topical delivery. The optimized formulation showed enhanced physicochemical stability and moisturizing properties, as well as improved drug release compared to free tryptanthrin. In human keratinocyte cells, the liposomal lotion exhibited lower cytotoxicity than the free tryptanthrin and demonstrated higher skin residual. In the DNCB-induced atopic dermatitis mouse model, the tryptanthrin-loaded liposomal lotion produced therapeutic effects comparable to or greater than those of 1.0% hydrocortisone, without inducing adverse effects such as skin atrophy. Overall, the tryptanthrin-loaded liposomal lotion is presented as a promising and safe strategy for the topical treatment of atopic dermatitis.
Triple-negative breast cancer (TNBC) presents formidable treatment barriers due to dysfunctional vasculature and an immunosuppressive microenvironment. To address these challenges, we engineered a bioinspired near-infrared (NIR)-responsive copper–polyphenol nanoplatform, SCP, to implement a NIR-triggered “bridge-and-attack” therapeutic strategy. This nanoassembly was constructed through the coordination of salvianolic acid B (SAB) with copper ions and further stabilized by a polydopamine (PDA) shell. Upon NIR irradiation, SAB and Cu 2+ were co-released from SCP, enabling simultaneous vascular remodeling and tumor cell killing. The released SAB promoted vascular normalization, increasing pericyte coverage to 51.6% and alleviating tumor hypoxia, thereby facilitating intratumoral penetration and immune-cell infiltration. Meanwhile, released Cu 2+ , together with PDA-mediated photothermal activation, induced cuproptosis and immunogenic cell death (ICD). This combined remodeling of the tumor microenvironment enhanced CD8 + T cell infiltration and achieved a tumor inhibition rate of 88.5% in 4T1 tumor-bearing mice with favorable systemic biosafety. Overall, this interfacial nanomaterial design integrates vascular normalization, photothermal-enhanced cuproptosis, and immunotherapy, providing a promising materials-based strategy for TNBC treatment.
While calcium silicate (CS) remains a gold standard material for vital pulp therapy, its clinical efficacy is frequently compromised by an abrupt ion release during the initial setting phase that induces extreme alkalinity and acute cytotoxicity. We engineered electrospun poly-ε-caprolactone (PCL)/CS composite fibers to reconfigure CS hydration kinetics, achieving sustained and controlled ion release. In vitro evaluation using phase-specific eluates and defined pH/Ca2+ conditions demonstrated that CS eluates from the initial setting phase induced significant cytotoxicity and excessive NETosis in primary neutrophils, whereas PCL/CS eluates maintained both at control levels. Mechanistically, neutrophil extracellular traps (NETs) isolated from CS-stimulated neutrophils directly drove M1 macrophage polarization, while PCL/CS eluates promoted an anti-inflammatory and proregenerative macrophage phenotype. PCL/CS eluates, conditioned media from PCL/CS-treated macrophages, and PCL/CS nanofibrous substrates all promoted odontoblastic differentiation. In vivo validation using a rat molar pulp exposure model revealed that during the early host response (at days 2 and 7), CS provoked marked neutrophil infiltration and excessive NETosis, whereas PCL/CS attenuated the acute inflammatory response and promoted timely inflammatory resolution and M2 macrophage polarization. At 8 weeks, the PCL/CS group exhibited improved dentin-pulp regeneration characterized by organized tubular dentin and polarized odontoblasts, rather than amorphous osteodentin typically observed with CS. PCL/CS also mitigated furcal bone resorption. These findings indicate that immune modulation through tailored ion release via the NETosis-macrophage axis represents an effective strategy for supporting dentin-pulp complex regeneration.
