Transdermal and topical delivery systems (TDS) have emerged as the third-largest route of administration due to their ability to bypass first-pass metabolism and maintain stable plasma concentrations. Skin physiologically based pharmacokinetic (PBPK) models mechanistically characterize the percutaneous absorption process, predict local and systemic exposure, and enhance research and development efficiency through virtual clinical trials. This paper first elaborates on the theoretical foundation of skin PBPK modeling based on Fick's second law of diffusion and compares the model assumptions and application scenarios of four well-established and validated modeling platforms: Simcyp, GastroPlus, Skin-CAD, and PK-Sim. The findings indicate that Simcyp provides a refined depiction of skin physiological structure and is widely applied in clinical evaluation and special population prediction. GastroPlus focuses more on the mechanistic description of TDS formulations. Skin-CAD, as a specialized software, is extensively utilized for in vitro-in vivo extrapolation (IVIVE) predictions and formulation optimization. PK-Sim, as a freely accessible open-source software, has been used to investigate the physiological ontogeny of skin in pediatric populations. However, existing studies share limitations such as highly inconsistent model structures with varying complexity, challenges in acquiring accurate parameters, and a scarcity of physiological information for special populations. Future research should prioritize optimizing parameter acquisition methods and broadening physiological databases for pediatric, geriatric, and skin-lesion populations. Additionally, integrating non-invasive imaging technologies to construct high-precision 'digital twin' skin models represents a critical future direction. These advancements will drive the transition of PBPK models from descriptive tools to supportive instruments for individualized dosing and regulatory decision-making.
Diabetes mellitus, chronic metabolic disease marked by persistent hyperglycemia resulting from inadequate insulin production or impaired action. Despite advancements in glucose-responsive insulin delivery systems, challenges persist such as limited responsiveness to dynamic glucose fluctuations, in vivo biocompatibility, and production scalability with uniform performance. However, insulin-loaded microspheres combined with microfluidics-based technology improve the subcutaneous insulin reservoir and homogeneous microsphere production rate. This study presents a microfluidic-engineered glucose-responsive controlled-insulin release microsphere using Glucose oxidase (GOx) as the glucose-sensing unit and a hybrid carrier composed of poly (lactic-co-glycolic acid) (PLGA) and acid-sensitive acetalated dextran (Ac-dex). The microfluidic-based fabrication method ensured uniform and controllable microsphere size and stable performance with satisfactory batch-to-batch reproducibility. In Streptozotocin (STZ)-induced diabetic mice, the microspheres maintained normal blood glucose levels for at least 20 hours. Absence of additional treatment-induced organ toxicity, systemic inflammation, and low hypoglycemic index ensured that the formulation is safe. Besides, this study provides a promising strategy for closed-loop insulin therapy, with potential clinical applications in improving glycemic control and reducing the burden of diabetes management.
Despite considerable advances in cancer therapy, the intrinsic heterogeneity of malignant cells continues to compromise therapeutic efficacy with conventional monotherapies, driving the need for combination treatments to achieve more durable and complete responses. The limited efficacy of conventional chemotherapy is largely attributable to the immunosuppressive tumor microenvironment, which is frequently perpetuated by epigenetic mechanisms, including aberrant DNA methylation. To overcome these limitations, we hypothesized that Decitabine (Dac)-mediated sensitization could dramatically enhance Sorafenib (Sor)-induced ferroptosis, and to test this synergy, we developed an innovative biomimetic codelivery platform comprising polymer micelles loaded with Sor surface-coated with exosomes encapsulating Dac (Exo&PM/D + S). This platform facilitates codelivery, enabling Dac-mediated DNA hypomethylation to remodel the tumor microenvironment and promote Sor-triggered ferroptosis. In vitro, Exo&PM/D + S exhibited potent anti-tumor activity by concurrently enhancing DNA demethylation and ROS accumulation. In mouse neuroblastoma models, the system significantly suppressed tumor growth, stimulated antitumor immunity, and extended survival. Mechanistic studies confirmed that Dac potentiates Sor-induced ferroptosis through epigenetic modulation. Thus, Exo&PM/D + S represents a promising nanotherapeutic strategy that synergizes epigenetic modulation with ferroptosis induction for enhanced anti-tumor efficacy.
Infected wounds represent a significant clinical burden owing to persistent infection, excessive inflammation, and impaired tissue regeneration. To overcome these limitations, we developed a sprayable N-succinyl chitosan/Pluronic F127 (NSC/PF127) hydrogel incorporating MoO₂ nanoparticles, ciprofloxacin, and fibroblast growth factor-2 (FGF-2). At body temperature, the hydrogel rapidly transitions from a solution to a gel and responds to both pH changes and near-infrared (NIR) irradiation. MoO₂ exhibits NIR-mediated photothermal activity, while CIP and FGF-2 are released in a sustained and pH-dependent manner, thereby maintaining antibacterial efficacy and growth factor bioactivity. In vitro studies demonstrated excellent cytocompatibility and significantly enhanced fibroblast and keratinocyte migration. The combined photothermal effect and antibiotic therapy effectively suppressed bacterial growth and disrupted established biofilms. In a rat model of Staphylococcus aureus-infected full-thickness wounds, the hydrogel composite significantly accelerated healing, reduced inflammation, promoted collagen deposition and angiogenesis, and enhanced tissue regeneration. Biochemical and gene expression analyses further indicated reduced oxidative stress and improved tissue regeneration. This multifunctional, sprayable hydrogel combines targeted antibacterial action with sustained pro-regenerative signaling, offering a promising strategy for further preclinical investigations of infected wound management.
Currently, the commercial fixed-combination of two agents is facing several clinical challenges, including suboptimal intraocular pressure (IOP) reduction, which requires multiple daily administrations, compromised bioavailability due to rapid tear film clearance and nasolacrimal drainage, and preservative-induced ocular surface toxicity. To address these limitations, we intend to develop a novel preservative-free, long-acting fixed-combination formulation of carteolol hydrochloride and netarsudil dimesylate. This once-daily formulation demonstrates enhanced therapeutic potential through optimized physicochemical stability and extended ocular residence time in theory. However, commercialized netarsudil dimesylate is precipitated when the pH of the solution is above 5.4 or when carteolol hydrochloride is mixed with netarsudil dimesylate. Consequently, the preservative-free and long-acting fixed-combination carteolol-netarsudil containing hydroxypropyl methylcellulose (HPMC) as a thickener (FC-CN-TKN) was prepared in a pH about 5.0 solution using an extremely simple one-pot pH-adjusting solubilization strategy, achieving stable co-solubilization of both active pharmaceutical ingredients. The optimized FC-CN-TKN formulation demonstrated excellent physicochemical stability under refrigerated storage conditions. Additionally, FC-CN exerted no influence on the intraocular penetration of each active compound in the pharmacokinetic study, and HPMC-mediated viscosity enhancement significantly prolonged precorneal retention, further improving its residence time and bioavailability. Importantly, once daily, FC-CN-TKN exerted a potent IOP-lowering effect and protective effect on retinal ganglion cells. The innovative FC-CN-TKN was stable, safe, and effective, being a promising glaucoma therapy.
Extracellular vesicles (EVs) have emerged as promising tools for early cancer detection, therapeutic monitoring, and drug delivery in oncology. Artificial intelligence (AI), particularly machine learning and deep learning, offers new analytical tools and computational approaches for EV research. This review summarizes recent advances in the application of AI to EV isolation, characterization, diagnosis, and drug delivery, with particular emphasis on its potential to enhance tumor detection sensitivity, diagnostic accuracy, and the rational design of delivery platforms. Special attention is given to the roles and recent applications of AI models in integrating multimodal features, characterizing EV heterogeneity, supporting diagnostic classification, and modeling in vivo behavior. Moreover, we examine the integration of AI with EV-based microfluidic isolation, surface-enhanced Raman spectroscopy (SERS), fluorescence imaging, and multiomics analysis. Among these areas, AI-assisted EV diagnostic applications are comparatively closer to clinical translation, with several studies incorporating patient-derived samples and AI-assisted diagnostic platforms, whereas AI-guided therapeutic EV design strategies remain largely exploratory. With the continued accumulation of multicenter, cross-platform EV datasets, improvements in algorithmic robustness, and closer integration of computational and experimental workflows, AI may support further clinical evaluation of EV-based diagnostics and the systematic optimization of therapeutic EV platforms.
Messenger RNA (mRNA) therapeutics have revolutionized biomedicine by enabling direct in vivo programming of immune cells. This strategy bypasses the complex manufacturing and high costs associated with ex vivo cell therapies. However, efficient and specific systemic delivery of mRNA to target immune cell subsets remains a major translational hurdle. This review systematically examines engineering strategies that address this challenge. We first outline the key biological barriers to mRNA delivery, such as serum instability, nonspecific biodistribution, cellular uptake heterogeneity, and inefficient endosomal escape. Next, we comprehensively review advances in lipid nanoparticle (LNP) engineering, including discovering novel lipids, modulating compositions, conjugating targeting ligands, and incorporating stimuli-responsive elements, to enable enhanced tropism toward specific immune cells. Representative applications in oncology, protein replacement, autoimmune disease, and tissue regeneration are highlighted. Finally, we address translational challenges in safety, scalable manufacturing, and regulatory issues. The integration of rational material design, high-throughput screening, artificial intelligence, and interdisciplinary collaboration will be essential to advance next-generation targeted in vivo mRNA cell therapies toward clinical translation.
The expanding clinical use of Antibody-Drug Conjugates (ADCs) necessitates a clearer understanding of their real-world toxicity profiles across diverse clinical settings. This retrospective pharmacovigilance study analyzed 19,697 adverse event (AE) reports for seven approved ADCs from the FDA Adverse Event Reporting System (FAERS) database (Q1 2004 to Q1 2025). Using disproportionality analysis validated by multivariable logistic regression, we identified safety signals for both monotherapy and combination regimens. The analysis revealed that toxicity profiles are strongly driven by an ADC's molecular structure and treatment setting. Target-specific ‘on-target, off-tumor’ effects were prominent, linking Nectin cell adhesion molecule 4 (NECTIN-4) targeting to skin reactions, Trophoblast cell-surface antigen 2 (TROP2) to gastrointestinal toxicities, and both folate receptor α (FRα) and tissue factor (TF) to ocular disorders. Furthermore, payload and linker types drove distinct toxicities; topoisomerase I inhibitors were associated with increased respiratory toxicity and mortality, while non-cleavable linkers conferred a significantly stronger risk of hepatobiliary toxicity. Combination regimens not only amplified specific risks, such as endocrine disorders with immune checkpoint inhibitors (ICIs), but also fundamentally reshaped toxicity kinetics, accelerating AE onset with ICIs while significantly delaying it with other combinations. This real-world analysis confirms that ADC toxicities are highly specific to their molecular design and clinical context, highlighting that understanding these complex structural and kinetic interplays is essential for optimizing safety management in clinical practice.
