Repairing bone defects in osteoporotic patients presents a significant clinical challenge due to inadequate osseointegration, persistent inflammation, and elevated oxidative stress. To overcome these barriers, this study proposes the development of a functionalized 3D-printed titanium alloy porous scaffold capable of sequentially releasing therapeutic agents to modulate the immune environment and enhance bone regeneration. A thermosensitive collagen hydrogel was integrated with a zeolitic imidazolate framework (ZIF-8) to construct a dual-release platform capable of delivering the immunomodulator 4-octyl itaconate (4-OI) and the osteogenic factor bone morphogenetic protein-9 (BMP-9) in a temporally controlled manner. The hydrogel facilitated early-phase release of 4-OI to inhibit M1 macrophage polarization and mitigate oxidative stress, while ZIF-8 enabled sustained BMP-9 release to induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Comprehensive in vitro assays and an osteoporotic rat model were employed to evaluate the scaffold's immunomodulatory properties, osteogenic capacity, and osseointegration performance. The scaffold inhibited pro-inflammatory cytokine expression, attenuated osteoclast activity, and enhanced osteogenic marker levels in vitro. In vivo analysis revealed enhanced bone-implant interface integration and significantly accelerated bone regeneration in osteoporotic defects. Transcriptome analysis revealed suppression of NF-κB and TGF-β signaling, confirming the scaffold's combined immunomodulatory and osteoinductive effects. This ZIF-functionalized hydrogel scaffold with sequential release capability offers a potential strategy for clinical translation in osteoporotic bone defect repair. By orchestrating local immune modulation and promoting sustained osteogenesis, the system offers a clinically relevant approach to enhance osseointegration and facilitate long-term bone repair in osteoporotic conditions.

Metabolic remodeling occurs during partial hepatectomy (PHx)-induced liver regeneration. Phospholipid remodeling during this process and its subsequent impact on liver regeneration remain unknown. The remnant liver's ability to defend against injury is also essential for normal liver regeneration, although the underlying mechanisms remain unclear. Phospholipidomics was performed to describe phospholipid remodeling after 70% PHx. Phosphate cytidylyltransferase 2, ethanolamine (PCYT2) was overexpressed in hepatocytes using adeno-associated virus under the thyroxine-binding globulin promoter. An liver perfusion system was used to regulate portal pressure. GalNAc-conjugated PEG-PCL nano-particles (NPs) were developed to deliver the PCYT2 inhibitor, meclizine. We found a significant decrease in a series of phosphatidylethanolamine (PE) levels at 1 day after 70% PHx. PCYT2, an enzyme for PE synthesis, was downregulated by PHx. Higher portal pressure-induced shear stress is an early event after PHx. As a target gene of hepatocyte nuclear factor 4α, PCYT2 levels were decreased by higher portal pressure. Hepatocyte-specific PCYT2 overexpression aggravated liver damage after PHx by increasing reactive oxygen species levels, lipid peroxidation, and mitochondrial fragmentation. We observed higher hepatic PCYT2 levels in middle-aged mice than in young mice. PCYT2 inhibition by meclizine facilitates liver regeneration in middle-aged mice. Meclizine is also a blocker of the histamine H1 receptor, a membrane receptor. Therefore, we used NPs to deliver meclizine into cells to better target PCYT2 and prevent potential side effects. NP-meclizine improved liver regeneration in middle-aged mice, demonstrating higher therapeutic efficacy than carrier-free meclizine. Decreased PCYT2 levels and PE content due to increased portal pressure protect hepatocytes from PHx-induced injury. Inhibiting PCYT2 with NP-meclizine promoted normal liver regeneration in middle-aged mice.

Disulfidptosis-a regulated cell death caused by disulfide stress under glucose starvation and high SLC7A11-offers a potential cancer vulnerability, but its regulatory landscape and therapeutic tractability remain unclear. We sought to (i) map disulfidptosis susceptibility across cancers, (ii) define associated pathways and regulators, and (iii) test whether targeting these pathways enhances disulfidptosis to improve antitumor efficacy. We curated 43 core regulators to compute the disulfidptosis score (D-score) across ~10,000 TCGA tumors, benchmarked with glucose-starvation datasets. Correlation screening yielded 506 candidate regulators, integrated into a refined score (D-score+). We associated D-score+ with hallmark pathways, genomic instability and DNA-repair signatures. Experimental validation used glucose-deprivation models, non-reducing immunoblotting and immunofluorescence of cytoskeletal proteins, CRISPR perturbations, and pharmacologic combinations with cell-cycle arrest agents and PARP inhibitors. Public clinical and drug-response cohorts supported translational analyses. D-score tracked experimental triggers (glucose starvation) and revealed cancer-type-specific prognostic patterns. D-score+ positively correlated with cell-cycle programs (e.g., G2/M checkpoint, spindle) and negatively with DNA-repair activity, while aligning with multiple genomic-instability signatures. Beyond F-actin, tubulin exhibited disulfide-dependent mobility shifts and microtubule disassembly. Combining disulfidptosis with cell-cycle arrest drugs synergistically increased cell death across models, with dose-responsive effects and cross-cancer activity. PARP inhibition synergized with disulfidptosis in multiple lines, and higher susceptibility tracked with PARP-inhibitor sensitivity datasets; CRISPR loss of ATM or FANCD2 further sensitized cells. D-score+ was lower in metastatic versus primary tumors and inversely related to EMT in select cancers; glucose starvation impaired migration in wound-healing assays. Inducing cell-cycle arrest and compromising DNA repair enhances cancer susceptibility to disulfidptosis, in part via redox-dependent disruption of actin and microtubules. D-score/D-score+ provide quantitative biomarkers to stratify tumors for combination strategies pairing disulfidptosis induction with cell-cycle inhibitors or PARP inhibitors. These findings nominate disulfidptosis-related pathways as actionable targets and support integrating disulfidptosis profiling into precision oncology, warranting and clinical validation.

Oligonucleotide-based gene therapeutics (OGTs) have emerged as a promising strategy for treating a variety of diseases, offering a tool for gene modulation at the mRNA level. Despite significant progress in OGTs development, their efficacy in both experimental and clinical settings has often fallen short of expectations. Current estimates suggest that less than 1% of transfected OGTs are released into the cytosol, significantly limiting the interaction with target RNA. Moreover, data suggests that only about 2% of the tested siRNAs achieve the expected 70% target gene knockdown . Clinically approved OGTs appear to be effective only against genetic disorders that lack effective alternative treatment, and even in these cases their therapeutic contribution remains marginal. Notably, the majority of approved OGTs, as well as those currently in clinical trials, are antisense oligonucleotides (ASOs) despite cell culture data showing that small interfering RNAs (siRNAs) exhibit greater potency. The delayed commercialization of siRNAs, despite high research interest, may be attributed to passenger stand-dependent off target effect and the immaturity of their design and modification strategies. This review critically evaluates the factors influencing therapeutic efficacy of OGTs and highlights the persistent gap between theoretical promise and clinical reality.

Myocardial ischemia-reperfusion (MI/R) injury induces apoptosis, metabolic dysregulation, and ventricular remodeling through complex pathological mechanisms. Although nanozyme engineering has the potential for antioxidation, reoxygenation, and pro-vascularization, achieving responsive modulation of the pathological microenvironment remains significantly challenging. A layered double hydroxide (LDH)-based nanozyme (ZnSrMo-LDH/Cu) was synthesized via a low-temperature hydrothermal/isomorphic substitution method for MI/R treatment. The reactive oxygen species (ROS) scavenging ability and responsive ion release performance of ZnSrMo-LDH/Cu were evaluated through various spectroscopic characterization methods. The biosafety and therapeutic efficiency of ZnSrMo-LDH/Cu-BSA nanozymes were assessed by and experiments. ZnSrMo-LDH/Cu demonstrated cascade superoxide dismutase (SOD) and catalase (CAT) activities, effectively overcoming acidic microenvironment limitations to maintain CAT activity rather than peroxidase (POD) activity while scavenging ROS to generate oxygen, with a ROS scavenging capacity 2.97 times that of FeO. Moreover, the acid-triggered Sr release promoted vascular regeneration and synergistically improved the ischemic-hypoxic microenvironment. Consequently, after bovine serum albumin (BSA) modification, ZnSrMo-LDH/Cu-BSA demonstrated excellent cytoprotective effects, reducing the cardiomyocyte apoptosis rates to 9.4% () and 20.7% () of the levels in the MI/R group. studies further validated that ZnSrMo-LDH/Cu-BSA enhanced cardiac function and attenuated ventricular remodeling by inhibiting oxidative stress and promoting angiogenesis. Mechanistically, ZnSrMo-LDH/Cu-BSA provided a cardioprotective effect by inhibiting the TGF-β signaling pathway, thereby alleviating cell damage caused by MI/R. The pathologically responsive LDH-based nanozyme represents a promising avenue for MI/R treatment.

Sustained hypertension induces adverse cardiac remodeling. Platelet activation is instrumental in exacerbating inflammation by engaging with macrophages. C-C chemokine motif ligand 5 (CCL5) is contained within platelet α-granules, and released following platelet activation. This work delineated the specific contributions of CCL5 to platelet function, platelet-induced macrophage polarization, and hypertensive cardiac remodeling. CCL5 knockout (KO) mice infused with Angiotensin II (Ang II) were used to identify the role of CCL5 . CCL5 absence on platelet activation were evaluated on washed platelets. Two distinct models of platelet depletion and reconstitution were utilized to investigate the impact of platelets lacking CCL5. An co-culture system was established to explore the roles of CCL5-mediated platelet activation in M2 macrophage polarization. CCL5 KO attenuated the adverse cardiac effects induced by Ang II, including fibrosis, hypertrophy, and functional impairment, accompanied by reduced platelet activation and M2 macrophage polarization in cardiac tissue. Platelet inhibitor administration and platelet depletion/reconstitution experiments revealed that the suppression of platelet activation by CCL5 KO contributed to the amelioration of Ang II-promoted cardiac M2 macrophage polarization and cardiac remodeling. CCL5 KO markedly suppressed the activation of TGF-β1 and NF-κB signaling, an effect observed both in cardiac tissue from Ang II-infused mice and in platelets following ADP stimulation . In co-culture systems, rmTGF-β1 reversed CCL5 KO platelet-impaired M2 macrophage polarization. NF-κB inhibition abolished recombinant CCL5 (rmCCL5)-induced platelet activation, while blocking antibodies against CCR1 and CCR3 inhibited rmCCL5-induced NF-κB signaling and platelet activation. These findings underscore the detrimental role of CCL5-mediated platelet activation in promoting M2 macrophage polarization during hypertensive cardiac remodeling and elucidate the molecular mechanism that CCL5 facilitates platelet-derived TGF-β1 signaling by promoting NF-κB activation CCR1 and CCR3 receptors. These findings support CCL5 inhibition as a promising strategy against inflammation and cardiac damage.

Melanoma management faces the dual challenge of preventing tumor recurrence while ensuring optimal post-surgical wound healing, particularly problematic given melanoma's high recurrence rates and therapeutic resistance. Artesunate (ARS) emerges as a promising multimodal agent with concurrent anticancer, anti-inflammatory, and tissue-regenerative properties. However, its anti-melanoma mechanisms remain incompletely characterized, and clinical translation has been limited by suboptimal pharmacokinetics. We employed transcriptomic profiling (RNA-seq) to identify novel ARS-regulated pathways. Subsequently, we developed an optimized drug delivery system comprising: amphiphilic nanoliposomes for efficient ARS encapsulation and enhanced cellular internalization, and a carboxymethyl chitosan hydrogel matrix (ARS-LS-Gel) engineered to provide sustained drug release while promoting tissue regeneration. Comprehensive physicochemical characterization preceded systematic evaluation in melanoma (B16F10, A375) and normal cell models, assessing cytotoxicity, cellular uptake, and mechanistic pathways. Dual efficacy was quantified using syngeneic melanoma and full-thickness wound healing models. The ARS-LS-Gel system demonstrated optimal physicochemical characteristics, including well-dispersed particles, sustained drug release kinetics and exceptional biocompatibility. It potently induced melanoma cell apoptosis through p53-mediated mitochondrial dysfunction, characterized by: (1) sustained ROS accumulation, (2) cytochrome C release, (3) mitochondrial membrane potential collapse, (4) impaired ATP synthesis, and (5) calcium overload. , the platform significantly suppressed tumor progression, evidenced by enhanced apoptosis and reduced Ki-67 expression. Concurrently, it accelerated wound regeneration via targeted downregulation of pro-inflammatory mediators (TNF-α, IL-1β) and enhanced collagen deposition. The ARS-LS-Gel platform's ability to simultaneously address oncogenic progression and tissue repair represents a significant conceptual and practical advancement in post-surgical cancer management. By bridging fundamental mechanistic discovery with engineered therapeutic delivery, our findings provide a robust foundation for imminent translational development in melanoma therapy and beyond.

Fibroblast growth factor 19 (FGF19), the human orthologue of murine FGF15, is an endocrine FGF that signals through the FGFR4-β-Klotho receptor complex to regulate bile acid synthesis, glucose and lipid metabolism, and thermogenesis. Beyond its physiological role in metabolic homeostasis, aberrant expression of FGF19 has been increasingly implicated in the initiation and progression of solid tumors. Mechanistically, FGF19 drives signaling cascades that sustain proliferation, invasion, and metabolic reprogramming, while also promoting epithelial-mesenchymal transition, angiogenesis, and immunosuppression to facilitate metastasis. These pleiotropic activities highlight FGF19 as a compelling therapeutic target, and several FGFR4-directed inhibitors have entered clinical evaluation. However, challenges remain, including on-target toxicities, limited selectivity and adaptive resistance. In this review, discuss the molecular mechanisms by which FGF19 shapes tumor biology, evaluate the current status of therapeutic strategies targeting the FGF19-FGFR4 axis, and explore future opportunities such as rational drug combinations and metabolic intervention. A deeper understanding of the interplay between FGF19 signaling, the tumor microenvironment and systemic metabolism will be essential to unlock its potential for precision oncology.

Pharmacological treatment of brain diseases is hampered by the blood-brain barrier that prevents the vast majority of drugs from entering the brain. For this reason, the pharmaceutical industry is reluctant to invest in the development of new neurotropic drugs. Even if effective pharmacological strategies for the treatment of brain diseases will be found, it will take 10-15 years between the emergence of an idea and the introduction of a drug to the market. This creates priority for the development of neuro-lymphaphotonics based on the development of promising non-pharmacological strategies for managing functions of the meningeal lymphatic vessels (MLVs). MLVs play a crucial role in the removal of toxins and metabolites from brain as well as in regulation of brain homeostasis and its immunity. Since MLVs are located on the brain surface, light penetrating the skull easily reaches MLVs and affects their functions. Therefore, MLVs are an ideal target for photobiomodulation (PBM). The pioneering studies have shown that PBM of MLVs is a promising strategy for the treatment of a wide range of neuropathology, including Alzheimer's or age-related brain diseases, brain tumor, intracranial hemorrhage, brain damages caused by diabetes. It has recently been discovered that sleep enhances the therapeutic effects of PBM and is a "therapeutic window" in overcoming the limitations of PBM in the elderly. Considering that the PBM technologies are non-invasive and safe with commercially viable possibilities (portability and low cost), neuro-lymphaphotonics open up promising prospects for the development of future technologies for the effective therapy of brain diseases.

Nanozymes, engineered nanomaterials with enzyme-like catalytic activity, are emerging as versatile tools in biomedicine due to their catalytic tunability and higher chemical, thermal, and structural stability compared to natural enzymes. While widely studied in oncology and inflammation, their potential in endocrine disorders remains comparatively underexplored due to the historical focus of nanomedicine on cancer-related oxidative stress, the complexity and heterogeneity of endocrine signaling networks that hinder direct translation, and the scarcity of preclinical models that capture the dynamic and systemic nature of endocrine physiology. However, disruption of hormonal homeostasis by free radical imbalance points to the significant potential of nanozymes in endocrine disorders. By mimicking redox-active enzymes such as catalase, superoxide dismutase, and peroxidase, nanozymes regulate reactive oxygen species (ROS), thereby influencing hormone biosynthesis, receptor sensitivity, and redox signaling. They also offer advantages such as composite architectures, targeted delivery, and integration into smart platforms like hydrogels and biosensors. This review explores the expanding role of nanozymes in endocrine and metabolic diseases, including diabetes, obesity, thyroid and adrenal dysfunctions, and reproductive disorders. We highlight advances in glucose biosensing, hormone detection, redox-targeted therapies, and regenerative approaches. Despite promising preclinical data, there is a lack of clinical trials and long-term biosafety assessments of nanozymes, underscoring the need for further translational studies. By bridging nanotechnology and hormonal regulation, we outline future research directions toward integrating nanozymes into endocrine diagnostics and therapeutics.

Targeted mRNA-lipid nanoparticles (LNP) show great potential for cancer immunotherapy by delivering neoantigen-encoding messages to tumor cells, prompting immune responses against tumors. However, the challenges of inefficient production of targeting ligand-grafted LNPs and the immunogenic effects of polyethylene glycol (PEG) hinder their therapeutic effectiveness. We introduced a simplified, one-step technique for creating PEG-free, human epidermal growth factor receptor 2 (HER2)-targeted mRNA-LNPs. This method incorporates self-assembled palmitoylated nanobodies (pNB), lipids, and mRNA that encode spike proteins (SP). We engineered cells to produce pNB, which were then mixed with lipids and mRNA at various ratios. Through hydrophobic interactions between the lipid tails and the palmitoyl groups, we assembled tumor-targeting mRNA-LNPs. We optimized both the lipid components and the quantity of pNB, and determined the optimal formulation based on a series of physicochemical characterizations of the LNP as well as in vitro cel assays. Building on this, we further conducted in vitro cytotoxicity assays targeting SP-expressing cells, followed by in vivo immune killing experiments. In vitro, SP-expressing tumor cells triggered strong immune responses and effective tumor cell destruction. Additionally, these pNB-LNPs demonstrated improved tumor-specific delivery, extended tumor retention, and considerable tumor volume reduction in vivo. This streamlined, PEG-free LNPs platform that utilizes pre-existing immunity presents a flexible strategy for targeted cancer immunotherapy and applications in infectious diseases.

: Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD) through the AKI-to-CKD transition; however, effective treatment strategies remain challenging due to the complex and multifactorial pathophysiology of this process. This study aims to develop a multifunctional nanoplatform for kidney-specific targeting, reactive oxygen species (ROS) scavenging, and anti-fibrotic drug delivery to mitigate AKI-to-CKD progression. : Reduced graphene oxide (rGO) was conjugated with hyaluronic acid (HA) to form HA/rGO nanoparticles, enabling CD44-mediated renal targeting and ROS-responsive drug release. Paricalcitol, a hydrophobic anti-fibrotic agent, was loaded onto HA/rGO to form P/HA/rGO. The physicochemical characteristics, ROS-scavenging capacity, and oxidative stress-responsive drug release were evaluated. cytoprotection was assessed using HK-2 cells under oxidative stress. studies using ischemia/reperfusion (IR) injury mouse models assessed biodistribution, renal targeting, and therapeutic efficacy after systemic administration of P/HA/rGO. : HA/rGO nanoparticles demonstrated potent antioxidant activity and significantly protected HK-2 cells from ROS-induced cytotoxicity. P/HA/rGO exhibited a high paricalcitol loading efficiency (93%) and released 26% of the drug over 30 days under oxidative conditions. P/HA/rGO selectively accumulated in IR-injured kidneys via HA-CD44 interactions, decreased serum NGAL and cystatin C levels, and effectively attenuated tubular injury, fibrosis, inflammation, and apoptosis compared to vehicle-treated controls. : The P/HA/rGO nanoplatform enables kidney-targeted delivery of paricalcitol with ROS-scavenging and ROS-responsive release properties, providing a promising therapeutic strategy to suppress the AKI-to-CKD transition via integrated targeting and microenvironment-responsive therapy.

Developing therapies for complex brain diseases faces significant challenges due to biological complexity and the stringent blood-brain barrier. While nanomedicine holds promise, traditional R&D paradigms suffer from inefficiency. This review introduces an intelligent theranostic paradigm that integrates high-fidelity brain organoid models, high-throughput screening (HTS/HCS), and Artificial Intelligence (AI). In this closed-loop workflow, organoid platforms serve a diagnostic role, generating predictive data on nanomedicine performance. AI then provides therapeutic guidance by processing this data to drive rational drug design, synthesis, and interaction prediction. This AI-driven convergence is poised to significantly accelerate the development of precisely targeted and individualized nanomedicines, offering new hope for breakthroughs in treating brain diseases.

CD137 is a powerful T cell costimulatory molecule, and CD137 agonists are being evaluated for human cancer immunotherapy. Urelumab and utomilumab, are two agonistic anti-CD137 antibodies that are most advanced in clinical trials but suffer from liver toxicity and low potency, respectively. Here we describe the development of a new type and formulation of a CD137 agonist that combines high potency and a strong safety profile. The extracellular domain of recombinant human CD137 ligand (rhCD137L) was conjugated onto mesoporous silica nanoparticles (MSNs) of approximately 50 nm in diameter, and the ratio of rhCD137L to MSNs was optimized based on their ability to costimulate the cytotoxic activity of T cells. As nasopharyngeal carcinoma (NPC) cells often express CD137, the effect of rhCD137L-MSNs on T cell-mediated tumor cytotoxicity was evaluated using the NPC cell lines C666 and HK-1, each tested as CD137-expressing and -deficient variants. Results were compared with those obtained using MSNs conjugated with urelumab (ure-MSNs) or unconjugated urelumab. The biodistribution, therapeutic efficacy and toxicity of rhCD137L-MSNs were subsequently assessed in humanized mouse NPC models. rhCD137L-MSNs were of higher potency than ure-MSNs or unconjugated urelumab in inducing T cell killing of the NPC cell lines C666 and HK-1, of both CD137-expressing and -deficient phenotypes. C666-CD137 and HK1-CD137 cells were eliminated more efficiently than the CD137-deficient cells. , in humanized mouse NPC models, both rhCD137L-MSNs and ure-MSNs inhibited tumor growth, with rhCD137L-MSNs being slightly more potent. This was reflected in an increase in T cell activation markers and an increased infiltration of effector memory CD8 T cells into the tumor. In contrast to ure-MSNs, rhCD137-MSN treatment did not induce liver damage, thereby demonstrating a more favorable safety profile than ure-MSNs. This study identifies a formulation of rhCD137L on MSNs that combines high potency with excellent safety.

Endometrial regeneration remains a significant clinical challenge for women with intrauterine adhesions (IUAs), thin endometrium, or uterine factor infertility, conditions that severely impair fertility and reproductive outcomes. Traditional hormonal and surgical interventions often fail to restore the structural and functional integrity of damaged endometrial tissue. This review comprehensively examines integrative bioengineering strategies for endometrial regeneration, focusing on the synergistic applications of biomaterials, stem cells, organoids, and organ-on-a-chip technologies. Natural polymers such as collagen, gelatin, alginate, hyaluronic acid, and synthetic polymers including PCL, PLA, PGA, and PLGA have been comprehensively evaluated for their ability to mimic extracellular matrix, support cell proliferation, angiogenesis, and modulate immune responses. The incorporation of mesenchymal stem cells, extracellular vesicles, and growth factors into bioengineered scaffolds, such as hydrogels and nanofiber membranes, enhances regenerative efficacy. Furthermore, emerging platforms, such as endometrial organoids, 3D bioprinting, and organ-on-a-chip systems, offer physiologically relevant models for precision regenerative medicine. Innovations such as AI-assisted monitoring, 4D printing, and advanced drug delivery systems represent transformative approaches to overcome current therapeutic limitations. This review highlights the convergence of materials science, stem cell biology, and microengineering as a foundation for next-generation, personalized therapies aimed at restoring endometrial function and fertility. In addition, the review highlights biomaterial-based strategies as the foundation of endometrial regeneration, by detailing how natural polymers (e.g., collagen, gelatin, alginate, hyaluronic acid) and synthetic polymers (e.g., PCL, PLA, PLGA) support tissue repair structurally and by mediating biological functions. The integration of advanced technologies, such as 4D printing, AI-assisted monitoring, and stem cell-derived extracellular vesicle delivery has emerged as a transformative direction for overcoming current clinical challenges. Collectively, these approaches offer a next-generation therapeutic paradigm for restoring endometrial function and fertility.

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS), are characterized by progressive neuronal dysfunction and limited therapeutic options, largely due to the restrictive nature of the blood-brain barrier (BBB). Exosomes, naturally occurring extracellular vesicles (EVs), have gained attention as innovative drug delivery vehicles owing to their intrinsic ability to cross the BBB, minimal immunogenicity, high biocompatibility, and capability to carry diverse therapeutic cargos such as proteins, nucleic acids, and small molecules. Furthermore, exosomes can be bioengineered to enhance drug-loading efficiency and targeting specificity, positioning them as a versatile and effective platform for treating NDDs. In this review, we summarize recent advances in exosome biogenesis, secretion, and engineering, with an emphasis on innovative strategies for exosome isolation, drug loading, and surface modification. We further explore their roles in modulating neuroinflammation, promoting neural regeneration, and enabling precise therapeutic delivery. Critical challenges associated with large-scale production, quality control, and regulatory compliance under Good Manufacturing Practices (GMP) are also discussed. Collectively, these developments underscore the transformative potential of engineered exosomes in advancing precision therapies for neurodegenerative disorders and offer strategic insights into their clinical translation.

Reactive astrocytes form a chemical and mechanical glial scar that inhibits neuro-regeneration after stroke. Astrocyte heterogeneity is accompanied by changes in morphology and mechanical properties altering during scar formation after injury. This work aimed to elucidate the relationship between glial scar stiffness and astrocyte subtype transformation. Astrocyte-specific archaerhodopsin-3 and channelrhodopsin-2 knock-in C57BL/6J mice underwent distal MCAO. Atomic force microscopy, ultrasound elastography and synchrotron radiation were used to determine changes in glial scar stiffness. A proteomic analysis of astrocyte subtypes was performed using single-cell laser capture microdissection-MS. Furthermore, optogenetics was employed to reduce the glial scar stiffness, thereby facilitating neural regeneration following brain injury. Glial scar stiffness systematically increases following stroke and correlates with an increased number of Wnt7b fibrotic astrocytes. Furthermore, these results indicate that Piezo1 is the key regulator of astrocytic stiffness and anisotropy, which contributes to the glial scar stiffness in the peri-infarct area. The downregulation of Piezo1 expression promotes activation of the Wnt7b-Ca nonclassical signaling pathway to modulate cytoskeletal reorganization. Finally, the specific optogenetic inhibition of Ca signaling in astrocytes can effectively reduce glial scar stiffness by decreasing the proportion of Wn7b astrocytes, which further promotes neuro-regeneration and improves the recovery of motor function after ischemic stroke. This study successfully revealed astrocyte subtype transformation as a key determinant of glial scar physical barrier formation after stroke and highlighted Piezo1 as a potential therapeutic target for modulating the mechanical microenvironment post-injury.

Oxaliplatin resistance poses a significant therapeutic challenge in colorectal cancer (CRC), contributing to disease progression and poor clinical outcomes. There is an urgent need to identify novel molecular targets to overcome chemoresistance and inhibit metastatic dissemination. We conducted integrative multi-omics analyses to identify genes associated with oxaliplatin resistance in CRC and detected ARL4C, a small GTPase, as a candidate driver. Functional experiments, including gene knockdown/overexpression, mutant construction, cell viability, apoptosis, migration, and invasion assays, as well as mouse models, were used to evaluate the role of ARL4C. Signaling pathways were examined using proteomics and molecular biology techniques. We employed network pharmacology and molecular docking to identify ARL4C-targeting compounds and selected β-Lapachone for further validation. ARL4C was significantly overexpressed in oxaliplatin-resistant CRC tissues and correlated with poor prognosis and increased metastatic potential. Mechanistic studies revealed that ARL4C activates RAP1/PI3K-Akt-mTOR and RAC1/Arp2/3 signaling axes, promoting cell survival, epithelial-mesenchymal transition, and invasion. ARL4C also inhibited its own ubiquitination by regulating USP38, forming a positive feedback loop that enhanced protein stability following chemotherapy. β-Lapachone was identified as a direct ARL4C inhibitor that binds competitively at the LYS128 residue, disrupting USP38 interactions and promoting ARL4C degradation. Combination therapy with β-Lapachone and oxaliplatin significantly suppressed tumor growth, reduced metastasis, reversed drug resistance, and mitigated oxaliplatin-induced renal toxicity in preclinical models. Our study identifies ARL4C as a critical mediator of chemoresistance and metastasis in CRC. Targeting ARL4C with β-Lapachone restores oxaliplatin sensitivity and enhances therapeutic efficacy, offering a promising combinatorial strategy with strong potential for clinical translation in drug-resistant CRC.

Nanotheranostics have attracted significant research attention for their potential in improving glioma management through integrated diagnostic and therapeutic functions. However, the limited capacity for dynamic structural transformation of current nanotheranostics in the tumor microenvironment (TME) restricts theranostic outcomes. Herein, we report a semiconducting polymer (SP)-based nanochanger (TM-P@SPN) that demonstrates aggregation-enhanced self-programable theranostics in orthotopic glioma upon glutathione (GSH) response. The TM-P@SPN is prepared using a SP as a triple-functional component (fluorescence probe, second near-infrared photoacoustic probe, and photothermal sensitizer), -amyloid peptide domain (KLVFF)-linked PEG as an aggregation trigger switch, and transferrin modified manganese dioxide (TM) as a targeting theranostic agent. Upon GSH response in the TME, the TM-P@SPN disassembles to release PEG and Mn (II), enabling SP-KLVFF-mediated hydrophobic aggregation through hydrogen bonding, which consequently enhances both photoacoustic imaging (PAI) and photothermal therapy (PTT). Meanwhile, the released Mn(II) can be utilized for -weighted magnetic resonance imaging (MRI) and chemodynamic therapy (CDT). Moreover, both CDT- and PTT-induced immunogenic cell death effect and Mn(II)-activated STING pathway promote dendritic cells maturation, thereby triggering systemic immune effects. This TME-responsive nanochanger is successfully used for self-programable theranostics, including fluorescence imaging (FLI)-enhanced PAI-MRI and CDT-enhanced PTT-immunotherapy.

Osteoporosis is a major public health concern worldwide. As the predominant and long-lived bone cells, osteocytes serve as key regulators of bone remodeling and mechanotransduction. However, the molecular mechanisms underlying their regulatory roles remain poorly understood. The roles of talin1, a key focal adhesion protein linking integrins to the cytoskeleton, in regulation of osteocyte function and skeletal homeostasis remain unclear. Osteocyte-specific talin1 conditional knockout (cKO) mice were established, and their skeletal phenotypes were assessed through micro-CT, histomorphometry, and biomechanical analyses. Osteocyte senescence and molecular signaling were assessed by RNA sequencing analysis, immunostaining, and biochemical assays. Talin1-p53 interactions were characterized by co-immunoprecipitation and pull-down assay. Rescue experiments were performed using talin1 and p53 double KO mice. Talin1 expression in osteocytes was markedly reduced during skeletal aging in mice and humans. Osteocyte-specific deletion of talin1 disrupted FA integrity and dendritic networks, leading to severe osteopenia in weight-bearing bones and impaired bone mechanical properties. Talin1 deficiency altered the bone marrow microenvironment, suppressing osteoblast differentiation while enhancing adipogenesis. Mechanistically, talin1 bound and sequestered p53 in the cytoplasm for proteasomal degradation. Thus, talin1 loss enhanced p53 nucleotranslocation, inducing upregulation of p16 and p21 and osteocyte senescence. Importantly, genetic ablation of p53 in osteocytes rescued the low bone mass phenotype, defective bone formation, and excessive senescence caused by talin1 loss. This study identifies talin1 as a key factor governing osteocyte senescence and bone mass. We define a novel talin1-p53 axis that links impaired focal adhesion signaling to osteocyte senescence and bone loss, highlighting potential therapeutic targets for aging-related osteoporosis.

Acute glaucoma is triggered by sudden spikes in intraocular pressure, which induces retinal ischemia/reperfusion (RI/R), leading to hypoxia, oxidative stress, and ultimately PANoptosis in retinal ganglion cells (RGCs). Developing a therapeutic approach that simultaneously targets these events may offer a promising strategy for reducing secondary neuronal damage in acute glaucoma. We developed a reactive oxygen species (ROS)/hypoxia dual-responsive, biodegradable nanoparticle system (NPs) containing azo and thioketal bonds, designed to encapsulate melatonin (MT), a known endogenous antioxidant and PANoptosis inhibitor. The biocompatibility, biosafety, and therapeutic efficacy of MT-NPs were evaluated using an oxygen-glucose deprivation/reperfusion (OGD/R) R28 cell model and using a RI/R rat model. The NPs efficiently released encapsulated MT in response to hypoxic conditions and the presence of ROS. This controlled-release system improved both the biocompatibility and long-term retention of MT in the retina. MT-NPs effectively alleviated hypoxia, cleared excess ROS, and inhibited PANoptosis in RGCs following acute glaucomatous injury. Compared to direct MT administration, MT-NPs were more effective at protecting RGC axons and somas and facilitating restoration of visual function in rats with acute glaucoma. This simplified but multifunctional delivery system leveraged the widely available and safe compound melatonin in a highly efficient nanoparticle platform. This system offers potent neuroprotective effects to the retina preventing injury caused by acute glaucoma, and thereby providing a promising clinically translatable strategy for the treatment of glaucoma.