Phosphatidylinositol-4-phosphate (PI4P) is a low-abundance membrane lipid that plays crucial roles in lipid exchange and homeostasis, signal transduction, and vesicle trafficking. PI4KA, a type III phosphatidylinositol 4-kinase, catalyzes PI4P synthesis at the plasma membrane (PM). However, the mechanism by which cytoplasmic PI4KA is recruited to the PM to regulate PI4P levels in response to extracellular and intracellular signals remains unclear. We found that PI4KA is tightly associated with membranous organelles, including the endoplasmic reticulum (ER). In response to Ca[2+], the membrane tethering protein extended synaptotagmin 1 (E-Syt1) recruits ER-localized PI4KA to ER-PM junctions, facilitating its PM recruitment and the assembly of the enzyme complex. In hippocampal neurons undergoing synaptic potentiation, neuronal activity-induced PM localization of PI4KA and PM PI4P synthesis also rely on E-Syt1 function. Thus, E-Syt1-mediated PI4KA localization to ER-PM junctions serves as a critical mechanism by which Ca[2+] signaling regulates lipid metabolism at the PM.

Cancer is a major global health concern, characterized by uncontrolled cell proliferation and high mortality rates. Conventional chemotherapeutic agents often suffer from poor selectivity and systemic toxicity, limiting their clinical utility. Etoposide, a potent topoisomerase II inhibitor, is widely used to treat various types of cancers such as lung, testicular, and lymphomas. However, its clinical application is hampered due to low bioavailability and rapid clearance. To address, these limitations, nanocarrier-based systems such as liposomes and nanocochleates have been fabricated and explored. In the present study, etoposide was encapsulated within liposomes using the ethanol injection method. The optimized liposomal batch (ETNL5) exhibited favorable physicochemical properties such as entrapment efficiency (75.80 ± 1.26%), particle size (210.7 ± 0.15 nm), zeta potential (- 27.6 mV), and in vitro drug release of 92.34%. This formulation was further converted into nanocochleates (ETNC) using calcium-induced fusion with DMPG-Na and cholesterol. Pharmacokinetic evaluation demonstrated that ETNC significantly improved systemic exposure in regulated release format. ETNC showed the highest Cmax (0.50 ± 1.52 µg/mL) and AUC0-∞ (116.74 ± 9.16 µg·min/mL), along with extended half-life (150.88 ± 13.25 min) and MRT (240.14 ± 36.98 min), indicating prolonged circulation and reduced clearance (0.08 mg/(µg/mL)/min), while the tissue distribution studies revealed enhanced lung accumulation (28.99 ± 0.02 µg/g) with minimal off-target exposure, suggesting potential for site-specific delivery. Overall, ETNC provide a stable, efficient, and targeted drug delivery platform with promising potential for improving cancer therapy. Their ability to enhance bioavailability, reduce toxicity, and selectively target organs makes them a superior alternative to conventional formulations.

Osteoarthritis (OA) is the most prevalent degenerative joint disease and a leading cause of pain and disability, yet current treatments remain largely palliative and fail to alter disease progression. Stem cell-based therapies offer a promising alternative, with mesenchymal stromal/stem cells (MSCs) representing the most clinically advanced approach. Preclinical and clinical studies demonstrate that MSCs exert anti-inflammatory, immunomodulatory, chondroprotective, and analgesic effects primarily through paracrine signaling rather than durable engraftment. Clinical trials consistently confirm intra-articular (IA) MSC safety and symptomatic benefit, though structural outcomes remain variable owing to heterogeneity in cell source, dose, and trial design. This recognition has fueled interest in cell-free derivatives, particularly extracellular vesicles (EVs), which recapitulate MSC paracrine functions while offering improved safety, scalability, and regulatory compatibility. In parallel, bioengineering innovations, including hydrogels, scaffolds, 3D bioprinting, nanotechnology, and genetic enhancement, are being leveraged to prolong persistence, optimize delivery, and enable adaptive, multimodal repair. Emerging sources such as induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), and joint-resident progenitors further expand the regenerative toolkit. These developments suggest that future regenerative strategies for OA may combine cellular therapies, cell-free products, and biomaterial delivery systems to improve treatment durability and therapeutic control.

Ramsay Hunt syndrome, caused by varicella-zoster virus reactivation, presents with facial paralysis, otalgia, and auricular vesicles. A Tanzanian woman with Grade VI facial palsy was treated with acyclovir and prednisolone, recovering to Grade II within 2 weeks. This illustrates dual therapy beyond the 72-h window may remain amenable to treatment.

Two recombinant bone morphogenetic proteins (BMP-2 and BMP-7) have received FDA approval for bone-related therapies. However, their clinical performance is limited by high costs, the need for supraphysiological doses, and adverse side effects. Here, we describe a chemically modified mRNA (cmRNA) encoding BMP-7 that promotes osteogenesis and functional ossification. The BMP-7 cmRNA is delivered using optimized lipid vectors and a composite fibrin-calcium phosphate scaffold. Among several lipids evaluated, two previously unexplored lipids efficiently condense mRNA and mediate its in vivo delivery. Transfer of BMP-7 cmRNA lipoplexes to human mesenchymal stromal cells activates intracellular vesicle transport and cytoskeletal remodeling, and regulates extracellular matrix production and calcium-associated processes. These responses were accompanied by robust mineralization and activation of key osteogenic pathways. In vivo, BMP-7 mRNA-activated scaffolds promote the formation of ossified tissue, with the highest dose yielding the largest ectopic bony growth. We further observe concurrent angiogenesis and neurogenesis, demonstrating coordinated tissue regeneration. This platform enables effective in vivo mRNA delivery for bone healing and can be applied to other tissues, facilitating the development of mRNA therapeutics in regenerative medicine.

Bone remodeling is a mechanically adaptive process that integrates physical loading with immune regulation during homeostasis, repair, and disease. However, the traditional view fails to fully explain how mechanical and immune signals are coordinated across cellular compartments. Emerging evidence indicates that mechanical forces, immune responses, and extracellular vesicles (EVs) function as an integrated communication system rather than independent regulators. Here, we propose a systems-level framework termed the "mechano-immune-vesicle regulatory circuit". In this framework, biophysical cues regulate EV biogenesis and selective cargo sorting through mechanotransduction pathways. These mechanically primed EVs then serve as communication vectors that reprogram osteoimmune responses, specifically by directing macrophage polarization, adaptive immunity, and bone-resident cell differentiation. The resulting immune output feeds back to reshape EV signaling and mechanosensitivity, suggesting a closed regulatory circuit that governs bone remodeling. By synthesizing advances in mechanobiology, osteoimmunology and EV biology, this review reframes bone remodeling as a mechano-immune-vesicle regulatory circuit rather than as a collection of parallel pathways. We further discuss how this framework may guide the design of mechano-responsive biomaterials and engineered EV-based therapies with spatiotemporal control over inflammation and bone regeneration. This conceptual integration provides a mechanistic basis for understanding bone diseases and for developing next-generation regenerative strategies.

A 65-year-old gentleman presented with a three-year history of burning, itching, and splitting of the scrotal skin. He had previously been treated with topical corticosteroids, emollients, antifungals, and multiple short and long courses of antibiotics, with limited response. A biopsy was performed, which confirmed a diagnosis of Hailey-Hailey disease (HHD). HHD is an autosomal dominant genodermatosis characterised by vesicles that form eroded, erythematous plaques with painful rhagades in flexural areas. Oral naltrexone has been used to treat alcohol use disorder and opioid use disorder for many years. Naltrexone is known to block opioid receptors and indirectly antagonize toll-like receptor 4 in the microglial cells of the central nervous system and peripheral macrophages. This potentially reduces inflammation due to a decrease in the production of substance P, tumour necrosis factor, interleukin-6 (IL-6), and other pro-inflammatory cytokines. In 2022, acitretin was commenced and uptitrated to 25 mg once daily. Unfortunately, his condition deteriorated, with extensive erosions affecting the groin and scrotum, and the patient also developed side effects from the medication. A surgical opinion was sought, but surgery was not considered suitable. Courses of prednisolone did not help. Other immunosuppressive agents, such as methotrexate, cyclosporine, and azathioprine, have been described in the literature with varying efficacy. After two years, the pain from his erosions had reduced his ability to walk. Naltrexone 2.5 mg was commenced and subsequently uptitrated to 5 mg. Six weeks later, the patient had an 80% improvement in his condition. The patient experienced no side effects from the treatment and required no blood monitoring. This gentleman with severe HHD predominantly affecting the scrotum was commenced on oral naltrexone. Naltrexone is postulated to work due to its analgesic and anti-inflammatory effects. It is a well-tolerated treatment for severe HHD that has drastically improved both our patient's skin and his quality of life.

Neuroinflammation and neurodegeneration are strictly related phenomena, characterized by dysregulation of microglia, central nervous system (CNS) resident immune cells. Interleukin-4 (IL4) has shown beneficial abilities to re-establish microglial homeostasis in experimental models of CNS traumatic injury, stroke and multiple sclerosis, but its optimal administration system remains uncertain. Here, we show that extracellular vesicles (EVs) released by engineered murine microglia BV2 cells constitutively expressing IL4 induced a faster and enhanced anti-inflammatory phenotype in wild type BV2 cells (as assessed by IL4R downstream signalling), compared with soluble IL4. This effect was blunted by an anti-IL4 antibody, while it was not dampened by knocking out the IL4 receptor α subunit in EV-releasing BV2 cells, suggesting that IL4 was localized on the EV surface and did not necessitate to be co-conveyed with the receptor to exert its function. BV2 cells treated with EV-associated IL4, compared with soluble IL4, demonstrated delayed permanence of IL4R in the early endosome, suggesting amplified signalling effects. In conclusion, we here show that the association of IL4 with microglia-derived EVs improve its anti-inflammatory effect in an in vitro murine microglial model, which may inform on novel therapeutic opportunities to restore microglia in human disorders marked by neuroinflammation.

Reliable, reproducible, and standardized characterization of extracellular vesicles (EVs) remains a central challenge due to methodological variability across analytical platforms and intrinsic EV heterogeneity within and across biofluids. Here, we evaluated EVs isolated using ultracentrifugation from dedifferentiated liposarcoma-conditioned media and commercially available healthy donor urine. Physical characterization and surface tetraspanin profiling of isolated EVs were performed using three widely used instruments: NanoFCM, CytoFLEX Nano, and ZetaView Evolution. All platforms consistently detected small EVs; however, absolute size distributions, particle concentrations, and tetraspanin expression levels varied, reflecting differences in optical configuration, detection principles, and fluorescence background sensitivity. Additionally, EV-associated DNA was quantified using two different methods, revealing further variability in both the DNA yield and quantity. Together, the observations highlight the method-dependent nature of EV analyses and underscore the importance of carefully considering instrument-specific metrics for interpreting EV data across biofluids.

Liquid biopsy has emerged as an important diagnostic paradigm impacting care across multiple cancer indications. This is also an area of great interest in pediatric solid tumours, including those affecting the central nervous system (CNS). Of special concern are pediatric high-grade gliomas (pHGGs) due to the associated diagnostic complexities, poor outcomes and difficult access to tumour tissue, especially for midline lesions. In this commentary we discuss the applicability of different liquid biopsy analytes accessible in cerebrospinal fluid or blood to detect, monitor or molecularly diagnose pHGG, concentrating on the emerging biology of extracellular vesicles and particles (EVPs), as both biological mediators and sources of diagnostic information. We highlight the role of oncogenic pathways in shaping the profiles of EVPs in brain tumours, and we point to diagnostic opportunities associated with the discovery of oncohistones, as possible modulators of EVP landscapes in pHGG.

Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) are regarded as important "cell-free" therapeutic carriers due to their potential for immune regulation and tissue repair. However, their large-scale application is constrained by bottlenecks such as low secretion yields under conventional culture conditions. This study established a magnetically controlled dynamic mechanical stimulation platform to enhance MSC-sEVs production. Superparamagnetic Fe3O4 nanoparticles were embedded into polyacrylamide to form magnetic composite hydrogels. An variable magnetic field induced reversible deformation of the hydrogel, thereby applying periodic mechanical loading to adherent cells. Results demonstrate that, compared to conventional plastic substrates, dynamic loading on MSCs significantly increases sEVs secretion (up to approximately 5-fold) without altering typical vesicle morphology or size distribution. Mechanistic studies indicate that this stimulus induces upregulation of the mechanosensitive channel Piezo1 and the nuclear YAP signaling pathway, thereby promoting sEVs release. Inhibition of Piezo1 or YAP attenuated the enhanced production effect, supporting a dual-pathway synergistic model where "Piezo1-Ca[2+] promotes release, while YAP promotes multivesicular bodies (MVB) generation." This platform offers an economical, simple, and promising solution for efficient and controllable sEVs production.

In recent years, cell-derived vesicle-modified biomaterials (CDVMBs) have been considered a promising strategy to overcome the limitations of traditional biomaterials in tissue repair and regeneration. By combining biomaterial carriers with cell-derived vesicles, CDVMBs integrate the functional advantages of the carriers, including support for cell adhesion, colonization, proliferation, and functionalization, while also incorporating the bioactive properties of cell-derived vesicles. In this review, the term "cell-derived vesicles" refers to two distinct bioinspired components used for carrier modification: cell membrane vesicles, which mainly retain membrane-associated receptors and interfacial biological functions, and exosomes, which are nanosized extracellular vesicles enriched in bioactive cargos such as proteins and nucleic acids. Accordingly, CDVMBs can mimic either the surface biological properties of source cells or the signaling functions mediated by exosomal cargos, thereby promoting interactions with damaged tissues and stimulating tissue regeneration. Based on the biomaterial biomimetic strategy and vesicle source, CDVMBs are classified into cell membrane-camouflaged biomaterials (CMCBs) and exosome-modified biomaterials (EMBs). This review summarizes their engineering strategies, biological mechanisms, and versatile applications for tissue repair, and further discusses the current challenges and future perspectives for clinical translation. Taken together, the integration of biomaterial carriers with cell-derived vesicles establishes a versatile bioinspired framework for engineering regenerative microenvironments and advancing tissue repair and regeneration.