Pharmaceutics

In the last decade, notable developments have occurred regarding the application of membrane vesicles—encompassing extracellular vesicles (EVs, including exosomes, microvesicles, apoptotic bodies, and others), self-organized cellular-membrane-derived vesicles, and isolated cell-bound membrane vesicles, among others—as bioinspired drug delivery systems (DDSs). A collection of 10 papers on such advances was published in the Special Issue of Pharmaceutics entitled “Advances of membrane vesicles in drug delivery systems, 2nd Edition”. These papers investigate the Minimum Information for Studies of Extracellular Vesicles (MISEV), in vivo fluorescence imaging and tracking, in vivo specific tissue targeting, and the therapeutic application of membrane vesicles as DDSs in cancers, osteoarthritis, ocular disorders, intestinal disease, and kidney diseases. The present article briefly summarizes these related topics and provides novel insights into the research on membrane vesicles as DDSs.

Background: Chronic wounds, especially in diabetic patients, pose a significant clinical challenge due to current treatment limitations and an increasingly affected population. A major issue is the stalled inflammatory phase, which prevents proper healing. This study developed a novel co-delivery system to address the deficiency of growth factors and persistent inflammation in chronic wounds. Methods: Gelatin nanoparticles (NPs) were synthesized to carry curcumin, an anti-inflammatory compound. These curcumin-loaded NPs (NP/Curc) were then incorporated into gelatin methacrylate (GelMA) hydrogels to form a hierarchical delivery construct, nanoparticles encased within a hydrogel. These hydrogels were then cryogenically milled into microparticles (MPs) to carry human mesenchymal stem cells (hMSCs). The viability and growth of hMSCs on the surface of curcumin-loaded MPs were evaluated. The release of curcumin from various MP configurations was analyzed. The anti-inflammatory effects of the MPs were assessed by measuring pro-inflammatory cytokine expression in human monocyte THP-1 cells. Results: Curcumin directly loaded into hydrogels showed a rapid burst release within three days. In contrast, NP/Curc had a more sustained release profile. Curcumin incorporation did not adversely affect the cell-carrier functions of MPs. Conditioned media from hMSCs cultured on the plain MPs demonstrated anti-inflammatory effects in THP-1 cells. Low doses of curcumin released from the MPs also showed anti-inflammatory activity. The combination of hMSCs and curcumin exhibited an additive effect in reducing IL-8 expression by 4× in THP-1 cells. Conclusions: This study demonstrates the feasibility of co-delivering cells and curcumin without compromising the cell viability of hMSCs. Using gelatin nanoparticles as a carrier prolongs curcumin release, offering a sustained therapeutic effect. This strategy of hierarchical delivery of curcumin and co-delivery of cells represents a promising approach for treating chronic wounds by simultaneously providing growth factors and reducing inflammation.

Background/Objectives: Oral administration remains the most widely used route for drug delivery but is unsuitable for many central nervous system (CNS) therapeutics due to extensive hepatic first-pass metabolism and the restrictive blood–brain barrier (BBB). Acetyl salicylic acid (ASA), despite its neuroprotective and anti-inflammatory potential, exhibits poor brain bioavailability when delivered orally, limiting its therapeutic utility in ischemic stroke and chronic neurodegenerative conditions. Methods: This study reports the first use of three-dimensional (3D) bioprinting to develop brain-targeting ASA nanoparticle (NP)-loaded orally disintegrating films (ODFs) for direct systemic uptake and enhanced CNS delivery. The ODFs were fabricated using a CELLINK INKREDIBLE plus^® bioprinter and optimized for uniformity, rapid dissolution, and nanoparticle stability. Results: The films displayed consistent physicochemical properties (weight 10.86 ± 0.28 mg; thickness 0.47 ± 0.26 mm; pH 7.5–7.7) and disintegrated within 2.38 ± 0.28 min. In vitro testing on BEND3 brain endothelial cells confirmed biocompatibility, with no inflammatory response or cytotoxicity up to 62 µg/mL. In vivo biodistribution in murine models demonstrated substantial brain accumulation, achieving 14.15 ng/mg tissue following buccal administration. Conclusions: This work establishes a novel, non-invasive CNS drug delivery platform combining 3D bioprinting with ligand-functionalized ASA NPs to bypass hepatic metabolism and improve brain targeting. The rapid-dissolving ODFs demonstrated high reproducibility, safety, and effective brain deposition, highlighting their translational potential for neurological therapeutics. This approach may be extended to other small molecules with limited CNS penetration, offering a versatile pathway toward precision neuropharmacology.