Diabetic wound healing is hampered by a dysregulated pathological microenvironment characterized by excessive reactive oxygen species (ROS), persistent chronic inflammation, and impaired angiogenesis. To address these challenges, we developed an endogenously bioactive components-polymer matrix integration platform (P-MG@vEVs) via encapsulating vascular endothelial growth factor (VEGF)-stimulated endothelial extracellular vesicles (vEVs) into ROS-responsive microgels (P-MG). Endothelial cells were preconditioned with VEGF, and the resultant vEVs were isolated via differential centrifugation, with enhanced vesicle production and enriched angiogenic factors (e.g., VEGFA) that effectively promote endothelial cell migration and tube formation. P-MG@vEVs microgels composed of phenylboronic acid-modified sodium alginate were fabricated using microfluidic technology. Moreover, the microgels exhibited ROS-triggered degradation, enabling targeted and sustained vEVs release in the oxidative wound microenvironment. In vitro, P-MG@vEVs efficiently scavenged ROS, modulated macrophage polarization toward the anti-inflammatory M2 phenotype, and enhanced angiogenesis. In streptozotocin (STZ)-induced diabetic mice, P-MG@vEVs efficiently reprogrammed the damaged cutaneous microenvironment via regulating key signaling pathways (e.g., HIF-1, IL-17, NF-κB), thereby alleviating inflammation, restoring redox homeostasis, and facilitating neovascularization. These multifaceted effects significantly accelerate wound closure and skin repair, as evidenced by enhanced re-epithelialization and improved collagen deposition. Collectively, this platform integrates the intrinsic bioactivity of VEGF-preconditioned vEVs with the ROS-responsive delivery capability of the microgel carrier, offering a highly promising strategy for diabetic wound management.

Lipopolysaccharide (LPS) is recognized as a promising candidate for immunotherapy due to its potent immunogenic properties. However, this strong immunogenicity necessitates precise and protective delivery strategies to ensure safe and effective application. In this study, an ultrasonic probe-fabricated nanocapsule was first developed. Owing to the hydrophobic barrier provided by the system, LPS covalently linked methyl acrylated hyaluronic acid (HAMA-LPS) based surfactant-free emulsion polymerization occurred exclusively at the interface of monomer vesicles, resulting in the formation of a hollow-structured nanocapsule. This structure not only protected the immunogenic LPS from oxidative damage in free radical polymerization but also enabled the in situ loading of the hydrophobic photosensitizer chlorin e6 (Ce6). The prepared nanocapsules achieved a 1.53% loading rate of Ce6 and could effectively generate ROS under laser irradiation and undergo acid/enzyme-responsive release. Following cellular uptake by tumor cells, the nanocapsule underwent degradation mediated by hyaluronidase, leading to the release of LPS-Ce6. Subsequently, LPS-Ce6 anchored onto the tumor cell membrane via hydrophobic interactions and exerted photodynamic therapy upon laser irradiation. This therapeutic strategy elicited a robust immune response. On the one hand, photodynamic therapy compromised cell membrane integrity, thereby promoting the release of damage-associated molecular patterns. More importantly, the membrane-anchored LPS-Ce6 acted as an in situ antitumor vaccine, providing a focal point for monocyte and macrophage recruitment, while inducing macrophage polarization toward the M1 phenotype and stimulating the secretion of various antitumor cytokines. Both in vitro and in vivo experimental results demonstrated that the nanocapsule effectively inhibited tumor growth and generated a significant antitumor immune response.

Postoperative esophageal stricture remains a significant challenge following endoscopic submucosal dissection (ESD), with limited effective prophylactic options in clinic. Here, we report the development of an injectable and tissue-adhesive hydrogel drug delivery system composed of quaternary ammonium chitosan and polyethylene glycol (QCS-PEG), which was loaded with triamcinolone acetonide (QCS-PEG@TA), designed to mitigate post-ESD strictures. In vitro assays demonstrated that the hydrogel formulation modulated macrophage polarization and inhibited fibroblast migration. In an ESD-induced porcine esophageal stricture model, treatment with drug-encapsulated hydrogel efficiently suppressed esophageal stricture and promoted tissue repair, which were superior over drug or hydrogel alone. Histological and immunohistochemical analyses revealed that the administration of hydrogel formulation reduced fibrosis and inflammatory cell infiltration in esophageal tissues. These findings suggest that QCS-PEG@TA hydrogel provides mechanical support, inflammation-modulatory and pro-healing effects that collectively prevent stricture formation, offering a clinically translatable approach to improve therapeutic outcomes after ESD.

The management of uncontrolled hemorrhage in anticoagulant-associated patients and visceral trauma necessitates hemostatic agents that operate independently of classical coagulation pathways. Herein, we report a gelatin sponge patch by one-sided coating with N-hydroxysuccinimide (NHS) ester-functionalized poly (acrylic acid-co-N-succinimidyl acrylate) (PANS), which acts by formation of covalent and hydrogen bonding cross-links between polymer, blood proteins, gelatin, and tissue to seal the wound site and prevent hemorrhage during surgery. PANS exhibits robust lap-shear strength of up to 114.4 ± 8.7 kPa, enabling the PANS-GS composite to achieve effective wet-tissue adhesion, while macroporosity is preserved for rapid blood absorption. This dual-function design allows simultaneous physical sealing and platelet enrichment with reduced dependence on fibrin-mediated coagulation pathways. In rat hepatic laceration and femoral artery injury models, the composite sponge demonstrates superior hemostatic efficacy, with significant reductions in bleeding time and blood loss compared to clinically used sponges in both non-heparinized and systemically heparinized subjects. Critically, biocompatibility assessments reveal minimal cytotoxicity and hemolysis, while histopathological analysis indicates no significant increase in inflammatory response compared with commercial gelatin sponge. These results establish a coagulation-independent hemostatic strategy that integrates strong wet adhesion with preserved porosity, offering promise for managing anticoagulant-associated bleeding, visceral trauma, and complex battlefield injuries.

Myocardial infarction (MI) is characterized by severe oxidative stress, excessive inflammation, and profound mitochondrial dysfunction. Although mitochondrial transplantation offers therapeutic promise for MI, its clinical translation is severely hampered by the extreme fragility of donor mitochondria with rapid loss of functional viability after isolation. Here, inspired by the intrinsic cellular defense mechanisms against mitochondrial dysfunction, MOTS-c, a mitochondria-derived peptide (MDP), is selected and further conjugated with self-assembling peptide (Q11) to fabricate a hydrogel-based mitochondrial delivery system (MQgel@Mito) for cardiac repair after MI. It has been observed that MQgel significantly extends the survival of isolated mitochondria and maintains metabolic enzyme activity for at least 8 h. More importantly, MQgel not only shields donor mitochondria from oxidative stress and calcium overload, but also enhances mitochondrial internalization by macrophages through an adenosine 5'-monophosphate-activated protein kinase (AMPK)-dependent mechanism. Furthermore, MQgel@Mito facilitates metabolic reprogramming of macrophages by suppressing pro-inflammatory glycolysis and enhancing oxidative phosphorylation (OXPHOS), thereby attenuating M1 polarization. Additionally, MQgel@Mito maintains mitochondrial homeostasis, reduces reactive oxygen species (ROS), and rescues apoptosis of macrophages. In a rat MI model, MQgel@Mito reduces M1 macrophage infiltration and cardiomyocyte damage by delivering viable mitochondria, thereby improving cardiac function and limiting pathological remodeling. These findings establish a paradigm for mitochondrial protection and demonstrate macrophage immunometabolism as a viable therapeutic strategy for MI.

Intervertebral disc degeneration (IVDD) is the main pathological basis of chronic low back pain (LBP). Its complex pathological mechanisms make it difficult for single therapies to simultaneously restore the structure and function of the intervertebral disc (IVD). Simple cell injection therapy faces problems such as low cell survival rate and poor tissue integration. Therefore, synergistic therapies combining cells and biomaterials provide a new cell therapy strategy for the regeneration and repair of IVDD. This article aims to review synergistic regeneration and repair strategies based on cells and biomaterials, and reviews and analyzes the biomaterials for cell delivery. Next-generation functionalized biomaterials possess multifunctional biocomposite properties such as anti-inflammatory, antioxidant, and responsive properties. This article also introduces the types and applications of different cell sources and strategies to enhance therapeutic effects, such as gene modification, nanozymes, and the construction of three-dimensional (3D) cell spheres and organoids. Finally, the theoretical basis and possibilities for realizing personalized medicine are discussed in conjunction with 3D printing technology. Through deep synergy and integration of cells, tissue engineering, and the microenvironment, the regenerative microenvironment of IVD can be reshaped, providing a solution with potential for clinical translational applications in the treatment of IVDD.

Diabetic wound healing poses a major clinical challenge. One of the promising therapy, the flap transplantation surgery exhibited unsatisfactorily low flap survival due to the intertwined pathological barriers: impaired angiogenesis, excessive oxidative stress, and persistent inflammation, leading to poor tissue repair. While the therapeutic platforms based on extracellular vesicles (EVs) emerges as a promising treatment, its efficacy is often limited by the inadequate yield and rapid in vivo clearance. To address this challenge, this study developed a strategy centered on preconditioning human umbilical vein endothelial cells (HUVECs) with high glucose (HG) stress to produce HG-preconditioned extracellular vesicles (hEVs), which significantly improve production, enrich regenerative cargoes (e.g., HIF-1α, VEGF), and enhance homologous cellular internalization. The hEVs derived from HUVECs were encapsulated by microfluidically fabricated gelatin methacryloyl (GelMA) microgels to create GelMA@hEVs. The biodegradable and biocompatible GelMA microgels enabled a sustained hEVs release profile. Therefore, GelMA@hEVs exhibited significant efficacy improvement in promoting endothelial cell proliferation, migration, and tube formation critical for vascularization, mitigating reactive oxygen species, and modulating macrophage polarization toward a pro-reparative phenotype. Mechanistically, these therapeutic effects relied on activating the HIF-1α/VEGF pathway, a core axis for angiogenesis dysregulated in diabetes. In diabetic ischaemic flap models, GelMA@hEVs significantly improved flap survival, restored vascular perfusion, and facilitated tissue regeneration without systemic toxicity. Altogether, this work provides a generalizable strategy for diabetic ischaemic flap repair by combining engineered EVs as bioactive cargo with a microgel scaffold for sustained delivery, offering a promising in situ tissue engineering solution.

Mitochondrial dysfunction is linked to various diseases, such as ischemic syndrome and type 2 diabetes, primarily due to insufficient energy supply caused by low adenosine triphosphate levels. Mitochondrial transplantation therapy is an emerging therapeutic strategy that can supplement the respiratory capacity of damaged mitochondria, thereby addressing mitochondrial disorders at their root. However, poor viability after isolation from cells, difficulties in targeting delivery in vivo, and low cellular internalization efficiency constitute the major challenges for the clinical translation of mitochondrial transplantation. The integration of advanced biomaterial design may hold the key to address these issues and improve the therapeutic efficacy of mitochondrial transplantation. In this review, we summarize recent advancements in biomaterial‐assisted mitochondrial transplantation by protecting mitochondria during delivery, improving the targeting efficiency in vivo, and facilitating mitochondrial internalization. We also emphasize the importance of synergistic therapy of mitochondrial transplantation with other therapies. Finally, we discuss current issues and potential future directions of biomaterial‐assisted mitochondrial transplantation therapy, aiming to further promote its clinical translation.

Volumetric muscle loss (VML) overwhelms the endogenous regenerative capacity of skeletal muscle, leading to serious fibrosis, which further reduces muscle strength and severely affects patients' quality of life. While decellularized extracellular matrix (dECM) scaffolds offer tissue-specific biochemical cues for muscle regeneration, conventional decellularization protocols deplete critical glycosaminoglycans (GAGs), particularly chondroitin sulfate (CS), which are essential for growth factor sequestration and signaling pathway activation. Here, we developed injectable CS-glycosylated dECM microgels via microfluidic technology to restore GAG functionality to promote comprehensive muscle regeneration. We demonstrate that CS functionalization enhances myoblast adhesion, proliferation, migration, and differentiation in vitro. RNA sequencing analysis reveals that CS-mediated enhancement operates principally through activation of canonical Wnt/β-catenin signaling, with coordinated upregulation of downstream myogenic programs. In a rat tibialis anterior VML model, administration with high-CS formulations (H-CS@ECM) greatly promote muscle regeneration, function recovery and vascularization, with the muscle exhibiting enhanced-, blood perfusion, neuromuscular connectivity, and contractile protein expression at 8 weeks. Our findings suggest that CS-glycosylated dECM microgels possess significant translational potential as a minimally invasive and pro-regenerative implant material for VML repair. More broadly, this work establishes GAG modification as a generalizable design principle for enhancing dECM scaffold performance across diverse endogenous tissue regeneration applications, without the addition of exogenous growth factors, cytokines or drugs.

Blood vessel reconstruction is key for ischemic disease treatment by restoring microvascular perfusion and mitigating pathological tissue stiffening. During neovascularization, the mechanical and biochemical cues presented by the cellular-scale spatial heterogeneity of extracellular matrix (ECM) facilitate the endothelial cells (ECs) spreading and mechanotransduction, thereby driving angiogenesis. Therefore, developing ECM-mimetic proangiogenic biomaterials with compartmentalized spatial heterogeneity is highly desirable but challenging. Here, inspired by the spatially heterogeneous mechanical properties of natural tissues, we designed a series of microgel-annealed hydrogels (GMP) with compartmentalized stress heterogeneity. By integrating microfluidic-synthesized rigid microgels, the soft PRP-derived fibrin matrix was annealed with spatially mechanical domains that direct ECs-guided vascular morphogenesis through mechanotransduction, where rigid microdomains provide anchorage sites for cells adhesion, while soft interstitial matrix permits stalk cells migration and morphogenesis. In vitro, heterogeneous GMP hydrogel augmented ECs mechanotransduction via activating integrin β1-p-FAK-p-MLC signaling pathway and stabilizing VE-CAD/β-cat junctions, promoting 3D vasculogenesis and angiogenesis. In a rat myocardial infarction (MI) model, treatment with the heterogeneous hydrogel enhanced myocardial neovascularization, attenuated ventricular dilation and enhanced cardiac function. These findings not only provide valuable guidance for engineering proangiogenic biomaterials via ECM biomechanical mimicry, but also highlight the promise of spatially heterogeneous hydrogel with engineered mechanical cues essential for de novo blood vessel formation in the treatment of ischemic disease. Statement of Significance This work develops a proangiogenic hydrogel that mimics the spatially heterogeneous mechanical properties of the native extracellular matrix (ECM). By annealing rigid microgels into a soft fibrin matrix, we create a biomaterial with compartmentalized stress domains that guide endothelial cell behavior. This engineered heterogeneity promotes 3D vascular network formation by enhancing key mechanotransduction pathways and stabilizing cell-cell junctions. Significantly, in a rat model of myocardial infarction, the hydrogel enhances neovascularization, attenuates tissue damage, and improves cardiac function. Our findings highlight that recapitulating ECM biomechanical heterogeneity is a transformative strategy for engineering biomaterials to drive functional blood vessel regeneration, offering a promising therapeutic approach for treating ischemic diseases.

The amphiphilic balance between cationic and hydrophobic segmentsis a critical determinant of the trade-off between antibacterial activity and biocompatibility of membranolytic polymers. In tertiary amine-based systems, this balance is dynamic and exquisitely sensitive to the pH of the tissue microenvironment. To elucidate the relationship between polymer composition and antibacterial efficacy across a physiological pH range, we developed a library of polymeric proton-gated membranolytic switches (PPGMSs) composed of butyl methacrylate and various tertiary amines. These switches achieve precise, pH-activated antibacterial activity, which is governed by the equilibrium between cationic (protonated amine) and hydrophobic butyl methacrylate and deprotonated amine domains. The switching pH of these switches increases with a higher proportion of tertiary amine or a decrease in higher amine hydrophobicity. From this library, P(E60/B) emerged as a lead compound, demonstrating potent activity againstE. coliandP. aeruginosaunder acidic conditions, and minimal cytotoxicity toward mammalian cells at neutral pH (7.4). Mechanistic studies confirmed bacterial membrane disruption as the mode of action. Crucially, P(E60/B) exhibited significant efficacy in a murine peritonitis model, reducing bacterial loads in a dose-dependent manner. This work establishes PPGMSs as a versatile platform for designing precision antimicrobials that leverage microenvironmental cues for selective therapy.

Antimicrobial-resistant (AMR) Gram-negative bacteria emerge due to the overuse of antibiotics. Moreover, current bactericidal drugs or materials inevitably associate with the immunologic risks from the lipopolysaccharide (LPS) released by dead bacteria, which initiates and exacerbates chronic tissue-destructive hyperinflammation, leading to treatment failure. In this study, we describe an orchestrated pH-sensitive cationic polymer nanoparticle encapsulated with rifampicin and toll-like receptor (TLR) siRNA (RNP/siRNA) that exhibits antibacterial and LPS-detoxifying characteristics for treating infected diseases. Under acidic conditions, RNP/siRNA nanoparticle releases rifampicin and cationic polymers displaying synergistically inhibitory activity against AMR bacteria by disrupting bacterial membranes, and facilitating the entry of antibiotics. Furthermore, RNP/siRNA nanoparticle exhibits high cellular uptake and TLR knockdown efficiency, thereby detoxifying the etiological LPS in M1-type macrophages polarization and reducing proinflammatory cytokines. In a mouse pneumonia model, RNP/siRNA nanoparticle treatment inhibits bacterial growth, suppresses inflammation and reduces leukocyte recruitment. In a rat periodontitis model, the administration of RNP/siRNA downregulates proinflammatory cytokines expression and inhibits bone resorption. This work highlights the elevated LPS release is an early trigger of hyperinflammation during the antibacterial process of currently established antimicrobials. The RNP/siRNA nanoparticle represents a promising strategy by integrating antibiosis and immunomodulation in a cascading manner for the treatment of bacterial infections.

Exosomes as a unique drug delivery system provide a new choice for tumor therapy. However, the in vitro functionalization of exosomes and the process of circulating drug delivery can easily cause exosome degradation and drug loss, thus reducing the efficiency of drug delivery. In this work, based on the endocyto-fusion-exocytosis pathway of exosome formation, a multifunctional hyaluronic acid nanogel loaded with the antiangiogenic drug vatalanib and the near-infrared photothermal agent indocyanine green (ICG) was designed. Lysosome escape and photothermal therapy were combined to promote exosome production. Hyaluronic acid nanogels were endocytosed by tumor cells with CD44 mediation, forming intracellular vesicle-coated nanogels, which were subsequently degraded by hyaluronidase with high expression in tumor cells. Anti-angiogenic signals in intracellular vesicles were then delivered to vascular endothelial cells by exosomes through membrane fusion and exocytosis, which inhibited tumor angiogenesis to prevent tumor proliferation and metastasis. Cell experiments and tumor models demonstrate that our therapeutic strategy can achieve effective tumor inhibition.

Deep burn wounds present significant challenges to rapid healing due to their complex microenvironment, characterized by multiple bacterial infections, excessive oxidative stress and blocked angiogenesis. Herein, a skin-inspired biogel/nanofiber composite dressing composed of gelatin-based biogel and electrospun nanofiber membrane co-loaded with asiaticoside (AS) and ZnO is designed and prepared for regulating the wound microenvironment to accelerate deep burn wound healing. Sodium pyrrolidone carboxylate (PCA-Na) as a natural moisturizing factor is introduced into the gelatin solution to prepare a skin-inspired biogel with strong tissue adhesion, high mechanical strength and good water retention capacity. The sustained release of AS and zinc ions (Zn2+) co-loaded into nanofibers promotes antibacterial activity, anti-inflammatory effects, angiogenesis and collagen deposition. The composite dressing exhibits excellent adhesion to red blood cells and platelets, hemocompatibility and cytocompatibility. Furthermore, it also presents remarkable rapid hemostasis capability with the hemostatic time greatly shortened to 35 s and the blood loss significantly reduced to 71 mg. Notably, it can significantly shorten the healing time of deep burn wound to 17 days by rapidly absorbing wound exudate, promoting collagen deposition and new blood vessels regeneration. Consequently, the composite dressing represents a promising sustained co-delivery system for accelerating burn wound healing.

Periodontitis is a destructive and chronic inflammatory disease initiated and sustained by multiple proinflammatory mediators. Current therapies mainly deal with bacteria elimination, but directly addressing the over-accumulated multiple inflammatory mediators in the periodontal microenvironment still remains a substantial challenge for regenerative periodontitis treatment. Herein, inspired by blood coagulation, an off-the-shelf artificial blood clot hydrogel encapsulated with platelet-rich plasma (PRP) is reported to mitigate the deteriorative inflammatory environment in periodontitis. The hydrogel (CCS-RSF@PRP) with a hierarchical fibers-interwoven network structure, in which the activated platelets are enriched, is structurally similar to the native blood clot. Functionally, in addition to the function of enriching and releasing growth factors, CCS-RSF@PRP can remarkably scavenge reactive oxygen species (ROS), neutralize endotoxin lipopolysaccharide (LPS), and proinflammatory cytokines (TNF-α, IFN-γ and IL-1β), inhibit M1 macrophage polarization and induce M2 macrophage polarization, thus blocking the chronic inflammatory feedback loop in the periodontitis. In rat periodontitis model, CCS-RSF@PRP hydrogel significantly expedits the repair of periodontium by normalizing the periodontal immune-environment. The work highlights the importance of local immunomodulation in the treatment of periodontitis, and the engineered PRP-derived hydrogel can mimic and expand the structure and function of native blood clot, holding great promise in treating chronic inflammatory diseases.

Tissue healing is regulated by the immune system, and harnessing the endogenous regenerative capacity has recently become an active area of research. Regulatory T cells (Tregs) are a subset of adaptive immune cells known for their potent immunosuppressive abilities and crucial role in maintaining tissue homeostasis. The use of Tregs shows great potential as a clinical approach for promoting tissue repair and regeneration. However, systemic immune suppression induced by Tregs presents significant risks to patients, including increased susceptibility to infections, nephrotoxicity, and the development of lymphoproliferative disorders. In the case of peripheral nerves, especially those with long-gap defects, the efficiency of spontaneous regeneration diminishes or may even cease entirely due to the complex and precisely regulated microenvironments within the body. While the local application of Tregs has shown effective immune regulatory effects, much remains unknown about their impact and underlying mechanisms in nerve regeneration. We synthesized a nano artificial growth factor hydrogel scaffold incorporating a cyclic BDNF mimetic sequence, designed to specifically bind to its receptor and activate Schwann cells and nerve cells. The hydrogel scaffold encapsulating Tregs preserves their proliferative potential and key Foxp3 phenotype, mitigating functional impairments caused by their inherent instability and susceptibility to polarization. Importantly, we report that chitosan conduits filled with Tregs, supported by a BDNF self-assembled peptide hydrogel, promote peripheral nerve regeneration in a 6-mm sciatic nerve defect model in mice. In addition to effectively regulating angiogenesis and macrophage polarization, they directly accelerate nerve regeneration, myelination, and functional recovery. We have developed a biologic approach for neural applications that ensures preservation, stability, and the creation of biomimetic neural microenvironments. This paves the way for new, viable strategies to leverage biomaterial-mediated Tregs regeneration mechanisms in treating peripheral nerve injuries and advancing clinical translation.

Tumor-resident microbiotas critically influence breast cancer progression and metastasis. To simultaneously eliminate intratumoral bacteria and induce tumor cell death, we developed pH-sensitive nanoparticles (PEPCA@SPA/Fe3+ NPs) by encapsulating sparfloxacin (SPA)-ferric ion (Fe3+) nanoparticles (NPs) within an amphiphilic polyethylene glycol-poly (cinnamyl aldehyde) (PEPCA) copolymer assembly. The PEPCA@SPA/Fe3+ NPs exhibit dual functions including antibacteria and tumor ferroptosis induction. When PEPCA@SPA/Fe3+ NPs entered the acidic environment of tumor cells, SPA/Fe3+ NPs were released, which could effectively eradicate intratumoral bacteria and oxidize glutathione (GSH), thus inactivating glutathione peroxidase-4 (GPX4) and triggering lipid peroxidation and ferroptosis of tumor cells. In orthotopic breast cancer models, intravenously administrated PEPCA@SPA/Fe3+ NPs effectively accumulated in tumor tissues and suppressed primary tumor growth, and significantly reduced lung metastasis by remodeling the intratumoral microbiota. Furthermore, the PEPCA@SPA/Fe3+ NPs formulation well synergized with α-CD47 immunotherapy to activate antitumor immunity by promoting the maturation of dendritic cells (DCs), inducing M1 polarization of tumor-associated macrophages (TAMs), down-regulating regulatory T cells (Tregs) and enhancing cytotoxic T cells. Collectively, this nano-platform provides a promising strategy for concurrent microbial elimination and ferroptosis induction in cancer therapy.

Myocarditis is fundamentally characterized by the excessive infiltration of inflammatory cells (monocytes and macrophages) within the myocardium, posing a substantial risk of progressive cardiac dysfunction. Blocking the C-C motif chemokine receptor 2 (CCR2) pathway to curtail the infiltration of CCR2+ monocytes can suppress the immune response; nevertheless, these approaches may unwittingly impede the normal migration and activation of myeloid cells, potentially undermining the body's immune defenses. To address this backdrop, we designed itaconic acid liposomes (ITA-Lipo) to modulate the immune function of CCR2+ myeloid cells and thereby alleviate myocarditis. It was found that ITA-C4 Lipo could not only inhibit the differentiation of monocytes and macrophages into a pro-inflammatory phenotype but also significantly facilitate the hitchhiking migration toward the myocardium via enhancing the expression of CCR2. In the doxorubicin (DOX)-induced mice myocarditis model, ITA-C4 Lipo enhanced the homeostasis of myocardial cells and reduced relevant blood indicators. The cardiac function was recovered by improving left ventricular ejection fraction (LVEF) and ventricular fractional shortening (LVFS), resulting in the extension of overall mice survival. Anti-inflammatory pathway validation demonstrated that ITA-C4 Lipo can modulate the phenotype of macrophages and activate the KEAP1-Nrf2 pathway, reducing the expression of IL-1β. These findings underscore the significance of ITA liposomes in regulating the polarization of myeloid cells during their chemotaxis to the inflammatory focus, representing a promising therapeutic strategy for myocarditis.

Prodrug-based self-assembled nanoassemblies, with carrier-free structures and high drug loading, are garnering attention for chemotherapy. Additionally, the synergistic effects of prodrug nanoassemblies combined with multiple cell death pathways deserve further exploration. Ferroptosis has emerged as a powerful nonapoptotic cell death modality, showing significant potential for tumor inhibition. Therefore, prodrug nanoassemblies combined with ferroptosis inducers may achieve amplified antitumor efficacy. Herein, a GPX4 inhibitor (ML210)-loaded SN38 prodrug nanoparticle system is developed to enhance antitumor efficacy via ferroptotic-chemotherapy synergy. In this system, SN38 is conjugated to 1-octadecanol by a disulfide linkage to construct the self-assembly prodrug. DSPE-PEG2k is applied to stabilize nanoassemblies. It is proven that ML210 is successfully encapsulated into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibit good stability and a GSH-responsive release profile. Furthermore, ML210-loaded nanoassemblies show stronger cytotoxicity, greater proliferation inhibition, and obvious ferroptosis activation. In the CT26 mouse model, ML210-loaded prodrug nanoassemblies demonstrated superior antitumor effects. The strategy-using prodrug as "carriers" for ferroptosis inducers-offers a promising approach for synergistic antitumor therapy.

Synovial tissue infiltration by pro-inflammatory macrophages is a critical factor in the pathogenesis of rheumatoid arthritis (RA), correlating strongly with high disease activity scores in affected joints and often lead to progressive joint damage and disability. Methotrexate (MTX) is the frontline therapeutic drug for RA, but its efficacy is hampered by short plasma half-life, reduced bioavailability, and severe adverse effects. To address these limitations, we developed an injectable polymer-nanomedicine supramolecular hydrogel (PNSH) with dynamic mechanical properties and morphology tailored for intra-articular administration and sustained drug release with minimized off-target toxicity. The hydrogel was assembled from MTX-loaded polymeric nanoparticles chemically conjugated with partially oxidized glucomannan. In vitro and in vivo studies demonstrate that PNSH exhibits low cytotoxicity and superior biocompatibility. It supports the sustained release of MTX, which promotes M1 macrophage remodeling towards the M2 macrophage via switching IRF5 and IRF8 to IRF3 and IRF4 through the adenosine A2A receptor (A2AR) signaling pathway. In a rat arthritis model, PNSH effectively mitigated tissue-damaging inflammation and restored the articular immune homeostasis, thereby inhibiting arthritis progression. Notably, PNSH also upregulated CD73 and A2AR, key components of the extracellular purinergic signaling pathway, promoted the transcriptional expression of IRF3 and IRF4, and significantly decreased the transcriptional expression of IRF5 and IRF8, driving macrophage re-polarization towards M2 phenotype. These findings suggest that PNSH has the potential to serve as a novel drug delivery system for regulating inflammation and treating RA.