Codelivery of chemotherapeutic agents is often challenged by physicochemical incompatibility between co-administered drugs and the inability of conventional systems to achieve spatiotemporal control over drug release. Herein, anisotropic microgels were fabricated by an electrohydrodynamic co-jetting (EHDC) technique using PLGA as a sustained-release matrix and polyethyleneimine (PEI), along with a crosslinker, 1,2,3,4-butanetetracarboxylic dianhydride (BTDA), as a pH-responsive compartment, potentially enabling the compartmentalization of physicochemically incompatible drugs within a single platform. Two anticancer drug-loaded formulations, DGPI and DIPG, exhibited mean diameters of ∼11.3 µm and ∼6.15 µm, respectively, with high encapsulation efficiencies (∼90%) for both drugs. In DGPI, doxorubicin hydrochloride was loaded in the PLGA phase and paclitaxel in the PLGA-PEI-BTDA phase, whereas the drug distribution was reversed in DIPG. FTIR, DSC, and TGA analyses confirmed molecular-level drug-polymer interaction and system stability, while CLSM validated the bicompartmental morphology, indicating the predominant localization of dual drugs within their respective compartments. In vitro release studies at pH 5.0, 6.5, and 7.4 revealed that DGPI exhibited a sequential release profile, whereas DIPG achieved codelivery with preferential pH-triggered release under acidic conditions and near-complete drug retention at physiological pH (7.4), indicating systemic stability. Furthermore, evaluation using 3D tumour spheroids demonstrated maximum therapeutic efficacy for the DIPG formulation, with a residual cell viability of ∼35%, attributed to simultaneous multi-pathway cytotoxicity. Overall, this work establishes an anisotropic microgel-based platform capable of programmable, spatiotemporally controlled codelivery of dual drugs for enhanced therapeutic outcome.

Pituitary neuroendocrine tumors (PitNETs), historically referred to as pituitary adenomas, comprise a heterogeneous group of neuroendocrine tumors with diverse hormonal phenotypes, molecular characteristics, and clinical behavior. Their management includes surgery, pharmacological therapy, radiotherapy, and, in selected refractory cases, systemic or molecularly targeted approaches. Advances in molecular endocrinology have identified recurrent alterations and dysregulated signaling networks, including GNAS, USP8, PI3K/AKT/mTOR, and MAPK-associated pathways, that contribute to the biological heterogeneity of PitNETs. This review summarizes the molecular mechanisms underlying PitNET development and examines established pharmacological therapies, including dopamine agonists, somatostatin receptor ligands, growth hormone receptor antagonists, and temozolomide, with emphasis on their mechanisms and clinical evidence. Emerging molecularly targeted approaches, including mTOR inhibition, EGFR-associated targeting, anti-angiogenic therapy, and immune checkpoint inhibition, are discussed according to their current level of experimental and clinical evidence. The review also evaluates advanced drug-delivery strategies relevant to pituitary disease, including intranasal delivery, nanoparticle-based systems, liposomal carriers, receptor-targeted platforms, and sustained-release formulations. Particular attention is given to the distinction between clinically established delivery technologies and approaches that remain experimental or are supported primarily by evidence extrapolated from other therapeutic areas. Clinical trial evidence is further summarized to contextualize the efficacy, limitations, and translational status of current and emerging therapies. Together, these perspectives highlight the opportunities and remaining challenges in developing more precise pharmacological and drug-delivery strategies for the management of PitNETs.

Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, oxidative stress, lipid accumulation, and vascular inflammation, leading to cardiovascular events such as myocardial infarction and stroke. Increasing evidence suggests that dietary polyphenols may offer cardioprotective benefits by targeting key molecular pathways involved in atherogenesis. This narrative review summarizes current evidence on the mechanisms and therapeutic potential of dietary polyphenols in the prevention and management of atherosclerosis. Published experimental, clinical, and epidemiological studies were evaluated to assess the effects of antioxidants and dietary polyphenols on atherosclerosis. Evidence indicates that polyphenols, including resveratrol, quercetin, catechins, curcumin, and anthocyanins, influence redox homeostasis and LDL oxidation while modulating molecular signaling pathways involved in inflammation, lipid metabolism, endothelial function, and cellular stress responses. These compounds also modulate inflammatory signaling pathways, particularly nuclear factor-kappa B (NF-κB) and MAPK, reducing the expression of adhesion molecules and pro-inflammatory cytokines. Clinical studies and meta-analyses suggest potential improvements in endothelial function, lipid profiles, blood pressure, and inflammatory biomarkers following polyphenol-rich dietary interventions, although findings remain heterogeneous and are largely based on surrogate outcomes. Emerging nano-delivery systems and gut microbiota-targeted approaches may improve polyphenol bioavailability and therapeutic potential, but their clinical efficacy remains to be established. Overall, antioxidants and dietary polyphenols may provide complementary approaches for cardiovascular risk reduction; however, their clinical efficacy in atherosclerosis management remains uncertain. Further well-designed, long-term clinical studies are needed to clarify their therapeutic relevance, optimal dosing, and safety.

Parkinson disease is an ongoing neurodegenerative disorder, and both motor and non-motor symptoms are involved with the existing therapies having minimal effects on the disease but only symptom alleviation. The goal of this systematic literature review was to generalize up-to-date evidence on the next-generation pharmacological strategies to manage the symptoms and the disease in a patient with Parkinson disease. The review was based on PRISMA 2020 and included the analysis of peer-reviewed studies of human research published in 2015-2026 and retrieved in the key databases, such as PubMed, Scopus, Web of Science, and Cochrane Library. This included 30 eligible studies consisting of randomized studies, observational studies, and early clinical trials. The results show that, although dopaminergic treatment continues to play a central role in managing motor symptoms, new methods such as gene therapy, gene editing, stem cell-based regeneration, nanomedicine delivery systems, repurposed drugs, artificial intelligence-based precision medicine approaches have a good neuroprotective and disease-modifying potential. Nonetheless, the majority of new interventions are still in preclinical or first line clinical phase, with a defined subset of emerging gene-, cell-, and nanotechnology-based approaches evaluated only in animal or in-vitro models rather than in PD patients and associated with small sample size, invasive delivery, limited follow-up and lack of long-term safety information. In general, the review concludes by stating that there has been significant advancement in diversification of therapeutic targets and mechanisms, but rigorous large-scale biomarker-directed clinical trials are needed to translate these advances to effective and sustainable treatment of the Parkinson disease.

Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.

Nanotechnology has emerged as a transformative force in modern healthcare, particularly through the innovative use of nanobots for drug delivery. These microscopic, programmable devices are designed to navigate biological systems and deliver therapeutic compounds directly to targeted tissues or cells, thereby enhancing drug bioavailability and minimizing systemic side effects. This review explores recent advancements in nanobot technology, including their engineering with advanced materials, magnetic control systems, and programmable designs that enable precise, adaptable drug delivery. The implications of nanobots are profound, offering targeted interventions in oncology, neurology, and infectious diseases, along with the potential for personalized medicine and real-time monitoring of treatment. Despite the promising outlook, significant challenges remain in optimizing biocompatibility, propulsion mechanisms, and regulatory frameworks. This work highlights the need for interdisciplinary collaboration to refine nanobots' clinical applications and unlock their full potential in shaping the future of targeted therapeutic approaches.

Vision impairment is a significant global health issue, affecting people of all ages and notably influencing quality of life. One of the major challenges in treating eye diseases is the effective delivery of drugs, as the eye possesses unique anatomical and physiological barriers. Structures such as tear drainage, the tightly packed corneal epithelium, and the blood‑ocular barriers often hinder medications from reaching therapeutic concentrations. Conventional treatments such as eye drops, ointments, and oral medications frequently exhibit poor bioavailability and limited penetration into target sites, particularly in posterior segment diseases. This often leads to minimal therapeutic relief or requires frequent dosing, which can compromise patient comfort and adherence. Recent advancements in drug delivery technologies have shown promise in enhancing therapeutic efficacy, prolonging drug retention, and improving patient compliance. This review highlights the critical barriers in ocular drug delivery and emphasizes the urgent need for innovative strategies to address them. It comprehensively discusses emerging technologies, including nanotechnology, nanocomposite contact lenses, intraocular implants, microneedles, and gene therapy, focusing on their ability to improve drug delivery and retention in ocular tissues. Moreover, challenges associated with these innovative systems, including safety concerns, regulatory hurdles, and manufacturing constraints, are explored. Subsequently, proposed future directions include smart delivery systems, precision medicine, and efforts to ensure equitable access worldwide. Overall, this review provides an integrated perspective on the current advances and future hope of ocular drug delivery technologies for patients with chronic or vision‑threatening eye diseases.

The efficacy of oral drug delivery is often constrained by gastrointestinal physiological barriers and the hepatic first-pass effect, while conventional oral formulations lack the capability of targeted release at intestinal lesions, creating an urgent need for innovative functional delivery carriers. β-Glucan, an abundant natural polysaccharide, holds great potential for constructing intelligent oral nano/micro delivery systems, owing to its resistance to human digestive enzymes and its inherent dual immunomodulatory and microbiota-regulating properties. This carrier not only serves as an ideal protective vehicle but also bypasses the first-pass effect via M-cell-mediated lymphatic targeting and achieves site-specific drug release at pathological sites through its susceptibility to colonic microbiota enzymatic degradation. This review emphasizes the structural diversity, structure-activity relationships, and combined immunomodulatory/microbiota-modulating functions of β-glucan. It further explains how M-cell targeting and microbiota responsiveness are integrated to overcome gastrointestinal barriers for precise intestinal and systemic delivery. Recent advances in β-glucan-based nano/micro delivery systems for the treatment of cancer and inflammatory bowel disease are also highlighted. Finally, current challenges and future directions for β-glucan-based oral nano/micro delivery systems are outlined. In summary, the unique properties of β-glucan offer exciting new opportunities for targeted oral drug delivery.

Global aquaculture faces an escalating disease and antimicrobial resistance (AMR) crisis, exacerbated by climate-driven physiochemical shifts and intensive farming practices. The integration of artificial intelligence (AI) and structural biology, spearheaded by AlphaFold, represents a paradigm shift in aquatic pharmacology, transitioning the field from empirical trial-and-error to rational in silico design. This review critically evaluates the application of AI-driven tools in aquaculture drug discovery and vaccine development. We examine the evolution of AlphaFold in predicting complex host-pathogen interactions and facilitating de novo drug design. Concurrently, we highlight critical limitations stemming from the reliance on multiple sequence alignment (MSA) depth rather than mere PDB taxonomic composition, the unreliability of direct molecular docking due to apo conformations, and the dynamic nature of psychrophilic adaptations in aquatic environments. Furthermore, we assess next-generation structural vaccinology, including reverse vaccinology and pre-fusion antigen stabilization, alongside the integration of nanomaterial-based delivery systems to overcome aquatic pharmacokinetic barriers. The synergy of AI with CRISPR/Cas technologies and multimodal large language models (MM-LLMs) for disease management is also explored. Despite unprecedented computational capabilities, significant bottlenecks remain, including a severe lack of species-specific omics data, the indispensability of in vivo wet-lab validation, and lagging regulatory frameworks. Ultimately, realizing the potential of precision aquatic medicine requires developing aquaculture-specific databases, addressing the ecological risks of open-water deployment, and democratizing these technologies for small-scale farmers to ensure sustainable, equitable, and resilient global aquaculture.

Over the past 5 years, the number of antibody-drug conjugates (ADCs) entering the oncology market has surged. By contrast, the clinical use of immunoliposomes-nanoparticles that also employ antibodies as targeting agents (i.e., antibody-nanoconjugates, ANCs)-has yet to receive approval. One possible reason is the limited understanding of the relationship between ANC exposure and efficacy. To address this gap, we developed a pharmacokinetic/pharmacodynamic (PK/PD) model for a docetaxel-trastuzumab ANC. PK and PD studies were conducted in MDA-MB-231 tumor-bearing mice, divided into three treatment groups: (i) control, (ii) free docetaxel + free trastuzumab, and (iii) docetaxel-trastuzumab ANCs. PK data were obtained by fluorescence imaging and captured systemic and tumor distribution of ANCs, while PD data were based on tumor growth measurements. The PK model was built using data from the ANC group, and the PD model was developed across all three treatment groups, with a leave-one-out cross validation strategy for predictive evaluation. Treatment schedule simulations were then performed. Using a population nonlinear mixed-effects (NLME) approach, the final PK model included a central and a tumor compartment, each with independent elimination rates. Tumor growth dynamics were best described by a reduced Gompertz model coupled with a Simeoni resistance model. This model demonstrated strong predictive performance. Using only data from the first two treatment cycles (4 time points) and Bayesian estimation in the test set, it accurately predicted systemic and tumor ANC concentrations across the subsequent four treatment cycles, with a relative error (RE) below 15%. Prediction precision was further improved (RE < 5%) when data from one additional treatment cycle were incorporated. Similar performance was achieved for PD data, with tumor volume predictions exhibiting RE < 15% and RE < 7.5% when implementing data from two and three treatment cycles, respectively. The model was then applied to simulate alternative treatment schedules. Interestingly, while systemic exposure remained comparable across regimens, every-5-day administration yielded the greatest tumor exposure compared to daily, weekly, and every-35-day dosing (mean ± SD tumor AUC: 55.4 ± 10.9 mg/kg day vs. 47.6 ± 9.38 mg/kg day, 51.4 ± 11.5 mg/kg day, and 44.6 ± 10.0 mg/kg day, respectively, one-way ANOVA, p < 0.001), highlighting the importance of dosing frequency. Overall, these results illustrate how PK/PD modeling can refine intra-tumor PK understanding and support preclinical development of innovative formulations such as ANCs.

Hepatocellular carcinoma (HCC) is characterized by high heterogeneity, a complex tumor microenvironment, and multiple physiological barriers that limit conventional therapies and cause significant toxicity. Drug delivery systems (DDS), particularly nanoscale delivery systems, offer promising opportunities to overcome these obstacles through passive targeting, active targeting, and stimuli-responsive drug release. Nevertheless, despite substantial progress in preclinical research, the clinical translation of most DDS remains challenging. This review systematically outlines the pathophysiological rationale underpinning DDS design for HCC, including the aberrant vasculature, hypoxia, low pH, overexpressed enzymes and immunosuppressive features of the TME, as well as liver-specific barriers. Subsequently, we comprehensively evaluate the progress and limitations of passive targeting, active targeting, stimuli-responsive, and locoregional delivery systems. Furthermore, we dissect the core bottlenecks currently impeding clinical translation: tumor heterogeneity, the "interlocking chain" effect of multiple biological barriers, uncertainty of the EPR effect, multidrug resistance mechanisms, poorly defined long-term safety of nanocarriers, and the "valley of death" caused by discrepancies between preclinical models and human disease. Finally, we envision future directions: next-generation targeting strategies should focus on CSCs and metastasis; DDS must be deeply integrated with immunotherapy to remodel the immune microenvironment; biomimetic and bio-derived delivery systems may circumvent inherent limitations of synthetic carriers; multifunctional theranostic platforms enable real-time monitoring and personalized treatment; and establishing more clinically relevant animal models alongside personalized DDS design paradigms is key to accelerating translation. Our central argument is that the future success of DDS for HCC will no longer rely on the "showmanship" of individual technologies, but rather on a "systems engineering" approach grounded in a profound understanding of HCC biological heterogeneity, with the core objectives being precise spatiotemporal control of drug distribution and beneficial interactions with the host immune system.

The intestinal mucus barrier is a complex, dynamic hydrogel that plays a central role in host-microbiota interactions, nutrient transport, and protection against pathogens. Understanding its physicochemical properties has become essential for developing predictive in vitro and in silico models for drug delivery, microbiome research, and disease modelling. Over the past decade, advances in polymer chemistry, glycoscience, and microfluidics have enabled the development of increasingly sophisticated mucus models that mimic structural, rheological, and biochemical features of native intestinal mucus. This review provides a comprehensive overview of recent progress in gut-mucus chemical model development, focusing on mucin biochemistry, hydrogel-based synthetic systems, microphysiological platforms, and an introduction on computational modelling approaches. Special emphasis is placed on emerging strategies to reproduce mucus heterogeneity, viscoelasticity, and microbial interactions. We critically assess the strengths and limitations of current models and highlight future directions for improving physiological relevance, including multi-scale integration and personalized mucus modelling. This review aims to provide a framework for researchers developing next-generation mucus models for biomedical and pharmaceutical applications.