AIM:To develop and characterize a targeted nano drug delivery system (nano-DDS), specifically fluorescently labeled Angiopep-2-conjugated PAMAM nanoparticles (FITC-APP NPs), and to evaluate its targeting efficiency and therapeutic potential both in vitro and in vivo. MATERIALS AND METHODS:Angiopep-2 was chemically conjugated to PAMAM via MAL-PEG-NHS crosslinking chemistry, followed by covalent attachment of fluorescein isothiocyanate (FITC) to yield FITC-APP NPs. Using brain microvascular endothelial cells (BMEC), glioma cells (C6 cells), and HEK-293 cells as a negative control, cell adhesion, uptake, and transport behavior were assessed. The cytotoxicity and antitumor efficacy against C6 cells were evaluated comparatively with non-targeted FITC-PAMAM NPs. RESULTS:FITC-APP NPs exhibited an average hydrodynamic diameter of 32.23 ± 0.62 nm and a zeta potential of -4.36 ± 0.10 mV. Compared with non-targeted FITC-PAMAM NPs, FITC-APP NPs demonstrated significantly higher adhesion, uptake, and transport rates in BMEC and C6 cells, whereas no significant differences were observed in HEK-293 cells. Furthermore, FITC-APP NPs exerted stronger inhibitory effects on C6 cells and displayed enhanced antitumor activity in animal models relative to FITC-PAMAM NPs. CONCLUSION:These results not only provided data support for the targeting characteristics of FITC-APP NPs, but also provided a method reference for the targeting performance assessment of brain-targeted nano-DDS.
Artificial Intelligence (AI) has become a fundamental driver of scientific progress, particularly in disease diagnosis, drug development, and drug delivery optimization. The intersection of AI, drug design, and nanosystems for delivery is accelerating the advancement of personalized nanomedicines and innovative diananostic and therapeutic approaches. This narrative review explores the integration of nanotechnology and AI in healthcare, with emphasis on cancer treatment, drug discovery, antimicrobials, and nanotoxicology. Based on studies published between 2020 and 2025, the analysis highlights AI applications in molecular profiling, predictive models for antimicrobial resistance, and nanomaterial safety assessments. In oncology, AI combined with high-performance computing enables detailed molecular profiling, supporting personalized cancer therapies. Machine learning models are also applied to the design of antimicrobial drugs, prediction of antibacterial efficacy, and strategies to counter resistant strains. Furthermore, AI plays a critical role in nanotoxicology, predicting adverse effects of nanomaterials and interpreting complex toxicological data. The convergence of AI and nanotechnology is revolutionizing healthcare by providing more accurate diagnostics, tailored treatments, and improved safety evaluations. AI-driven models enhance drug discovery, optimize delivery systems, and strengthen toxicological assessments. However, continued research is necessary to refine these technologies and ensure their effective translation into clinical practice.
OBJECTIVE:This study aimed to develop chitosan-based nanoparticles (ChNPs) for Triptolide (TPL) delivery to mitigate intervertebral disc degeneration (IDD). METHODS:TPL-magnesium (Mg) ChNPs were prepared by mixing TPL, magnesium sulfate, and chitosan under controlled stirring, followed by nanoparticle characterization. An in vitro IDD model was established by stimulating nucleus pulposus cells (NPCs) with IL-1β. The therapeutic effect and biosafety of TPL-Mg ChNPs was assessed using cell counting kit-8. In an in vivo IDD rat model, pathology of intervertebral discs was evaluated via micro-computed tomography and histological staining. Western blotting, immunofluorescence, and immunohistochemistry were used to assess MAPK signaling, mitophagy activity, and extracellular matrix (ECM) programs. RESULTS:TPL inhibited the proliferation of IL-1β-induced NPCs. TPL was complexed with Mg2+, and further coated with chitosan via electrostatic adsorption to obtain TPL-Mg ChNPs. TPL-Mg ChNPs exhibited physical stability and biosafety, and could control drug release. TPL-Mg ChNPs were internalized by damaged NPCs within 4 hours and inhibited reactive oxygen species release. In vitro, TPL-Mg ChNPs protected NPCs and maintained ECM metabolic balance. In vivo, TPL-Mg ChNPs significantly improved IDD pathology in rats by inhibiting MAPK signaling and activating mitophagy. CONCLUSION:TPL-Mg ChNPs ameliorate IDD progression by inhibiting the MAPK pathway and activating mitophagy.
AIMS:Breast cancer (BC) remains the most prevalent malignancy in women, with conventional chemotherapy limited by drug resistance. This study develops a glutathione (GSH)-responsive nanoplatform combining chemotherapy with phototherapy against drug-resistant BC. METHODS:Gambogic acid (GA) was conjugated to carboxymethyl chitosan via disulfide bonds (GA-SS-CMCS, GSC), then loaded with graphene quantum dots (GQDs) to form GSC@GQD nanocomposites. The formulation was characterized by TEM, DLS, and NMR; photothermal performance, drug release, ROS generation, hemocompatibility, and anti-tumor efficacy were evaluated in MCF-7, MCF-7/ADR cells and MCF-7/ADR xenografts. RESULTS:GSC@GQD showed uniform morphology (~180 nm), GSH-triggered GA release (94% at 48 h), and hemolysis <5%. Under 808 nm irradiation, GSC@GQD raised temperature by 20 °C (vs. 9 °C for free GQDs), induced intracellular ROS accumulation, and achieved apoptosis rates of 86% (MCF-7) and 76% (MCF-7/ADR). In vivo, GSC@GQD + NIR suppressed tumor growth with satisfactory biosafety. CONCLUSIONS:GSC@GQD integrates chemotherapy, photodynamic and photothermal therapy into a GSH-responsive platform, offering a promising strategy against drug-resistant BC.
Pediatric respiratory diseases such as pneumonia, asthma, bronchiolitis, tuberculosis (TB), and cystic fibrosis (CF) are among the most important global health burdens and also main causes of mortality and morbidity in the pediatric population. The traditional therapeutic interventions are associated with considerable limitations, including systemic toxicity, inadequate lung targeting, rapid mucociliary clearance, and inadequate intracellular drug delivery, which limit their effectiveness. This review aims to provide an overview on cationic lipid-based nanocarriers (CLNCs), targeted pulmonary drug delivery, pediatric respiratory diseases, formulation strategies, therapeutic potential, safety considerations, and challenges for translation. The development in nanotechnology has indicated that cationic lipid-based drug carriers are promising drug delivery systems to target respiratory diseases. Solid lipid nanoparticles (SLNPs), cationic liposomes, lipid nanoparticles (LNPs), and nanostructured lipid carriers (NLCs) are examples of CLNCs. In addition, new advances in intelligent drug carriers and inhalable nanomedicines in nanoparticle development are improving the mechanisms of precision respiratory medicine. However, there are considerable limitations and challenges in immune activation, cationic lipid toxicity, lung barriers, stability, and scalability. The multidisciplinary research, especially designed for pediatric clinical trials, is important for converting these nanocarrier systems into safe and effective clinical treatments.
AIM:To develop and evaluate a lactoferrin (Lf)-functionalized polyethylene glycol (PEG)-grafted chitosan (CS) nanocarriers (NCs) for low-density lipoprotein receptor-related protein-1 (LRP1)-mediated intranasal delivery of lentinan (LNT) to enhance brain targeting and anti-glioblastoma (GBM) efficacy. MATERIALS AND METHODS:Lf-LNT-PEG-CS-NCs were prepared, optimized, and characterized for particle size, entrapment efficiency, coating efficiency, and release behavior. Ex vivo permeation, cellular uptake, cytotoxicity, apoptosis, pharmacokinetic, and biodistribution studies were performed using U87 MG cells and Wistar rats. RESULTS:The optimized NCs exhibited a particle size of 205.3 ± 11 nm, entrapment efficiency of 71.52 ± 0.98%, and coating efficiency of 92.42 ± 0.94%, with sustained drug release for 36 h. The permeation increased by 2.86-fold, while cellular uptake reached 78.38 ± 3.76%. Treatment significantly reduced U87 MG cell viability (84.21 ± 2.75% inhibition) and induced apoptosis with 64.55 ± 2.28% G0/G1 arrest, accompanied by reduced COX-2 (55.81 ± 2.91%) and Bcl-2 (59.65 ± 1.95%) expression and increased caspase-3 (73.10 ± 2.91%). Intranasal administration achieved a CSF Cmax of 46.72 ± 3.78 μg/mL and brain accumulation of 42.83 ± 2.59 μg/mL. CONCLUSION:LRP-1-targeted Lf-LNT-PEG-CS-NCs significantly enhanced intranasal brain delivery, cellular uptake, and apoptotic activity of LNT, demonstrating a promising noninvasive platform for targeted GBM therapy.
Intradermal (ID) delivery of mRNA therapeutics offers compelling advantages over intravenous administration, including minimally invasive self-administration, distinctive depot pharmacokinetics with dual lymphatic and vascular drainage, and direct access to the skin's dense immune cell network. While ID nucleic acid delivery has achieved clinical validation in inflammatory contexts such as vaccines and polynucleotide-based tissue regeneration, expansion into non-inflammatory applications such as protein replacement therapy, tolerogenic vaccines, and local antibody production is constrained by poorly understood physical and immunological barriers. This review examines the physicochemical challenges of transfecting dermal cells, including engineering nanoparticle interactions with the lymphovascular network, collagen matrix, and glycosaminoglycans. We then address the immunological landscape of the dermis, discussing cell-type-specific innate sensing by macrophages, dendritic cell subsets, and fibroblasts, and how nanomaterial chemistry shapes these responses. We propose that progress in ID immunoengineering requires mechanistic investigation of the nanomaterial-biological interface and innate immunogenicity resulting from mRNA delivery in human skin models. Strategies that selectively engage the innate immune system will transform the dermis from a barrier into an accessible interface for nucleic acid medicine.
Intranasal drug delivery has emerged as an attractive noninvasive route for local, systemic, and central nervous system (CNS) therapy due to its rapid absorption, avoidance of first-pass metabolism, and potential for nose-to-brain transport. However, the effectiveness of this route is limited by mucociliary clearance, mucus, enzymatic degradation, and poor epithelial permeability. Electrospun fibrous systems have gained increasing attention as intranasal platforms capable of simultaneously addressing these challenges through tailored polymer/excipient selection and formulation design. This review summarizes advances in electrospun intranasal systems and the influence of formulation characteristics on drug-mucosa interactions based on English-language articles identified through PubMed, ScienceDirect, and Google Scholar from January 2010 to May 2026, supplemented by manual reference screening. Mucoadhesive polymers improve drug retention, fast-dissolving polymers promote rapid release and sustained-release polymers prolong drug availability. Particular focus is placed on three complementary mechanisms employed to overcome nasal barriers: mucoadhesion, mucopenetration, and permeation enhancement, which improve nasal retention, mucus transport, epithelial permeation, and biomolecule stability. Recent studies support the potential of electrospun systems for local, systemic, and experimental nose-to-brain delivery, highlighting multifunctional nanofibrous platforms as promising candidates for future intranasal therapies.
Clinical management of inflammatory bowel disease (IBD) is hampered by limited therapeutic targets, primary non-response, secondary loss of efficacy, and safety risks, which undermine clinical outcomes. Probiotics and postbiotics represent promising preclinical candidates to alleviate these unmet clinical bottlenecks. Bacterial extracellular vesicles (BEVs) are naturally secreted bacterial nanovesicles carrying abundant bioactive cargos, whose bioactivity and safety are highly strain-dependent. Probiotics-derived BEVs can remodel gut homeostasis, repair epithelial barriers, and regulate mucosal immunity to suppress the inflammatory vicious cycle in IBD, while pathogen-/pathobiont-derived BEVs loaded with lipopolysaccharide and virulence factors exacerbate intestinal inflammation. Native BEVs are restricted by low cargo loading, poor gastrointestinal stability and inadequate colon tropism. Rational engineering strategies, including surface modification, self-loading hybridization, genetic manipulation, and pH-responsive coating, can optimize the therapeutic performance of BEVs. This review systematically summarizes BEVs biological mechanisms, engineering approaches, and translational obstacles and outlines prospects for the design of intelligent multifunctional BEVs and standardized large-scale manufacturing as future directions, providing theoretical support for oral BEVs nanotherapies against IBD.
Drug delivery in cornea remains a challenge due to its unique dome shape, anatomy, epithelial barrier, rapid drug clearance, and eyelid blinking. Nanoscale-based drug delivery systems are particularly attractive for treating corneal diseases due to sustained local drug release without major side effects. Nano drug delivery systems have potential to overcome many limitations including drug's residence-time, controlled-release, and solubility in the cornea. This review provides an overview of critical considerations for corneal nanomedicine development ranging from the nanoscale-design to achieving an optimal drug delivery with a discussion on cornea-specific biology and diseases. Herein, we discuss key anatomical features and drug transport challenges across the tear film, mucins/glycocalyx, epithelium, stroma, and endothelium that can influence nanoparticle behavior. Further, article outlines indication-driven target drug profiling; core physicochemical parameters related to drug retention, penetration, distribution, and safety; and factors affecting sterility, osmolality, tolerability, and pH, regulatory expectations, and manufacturing reproducibility. Overall, nanoscale drug delivery systems offer an attractive approach to treat corneal dysfunction without major side effects.
Conventional therapeutics (eye drops, injectables, ointments, gels) for ocular diseases face several challenges, including low ocular permeability, rapid clearance, low bioavailability, and off-target effects due to complex anatomical barriers and physiological ocular events. Nanomedicine can avoid some challenges of conventional delivery systems by offering prolonged ocular retention, site-specific targeted drug delivery, low toxicity, improved bioavailability, and therapeutic activity. Further, theranostic nanomedicines offer the advantages of diagnostic and therapeutic features during treatment. Carbon dots (CDs), also known as carbon nanodots (CNDs) or carbon quantum dots (CQDs), are ultra-low-sized, zero-dimensional nanomaterials with a diameter below 10 nm, and have received attention due to their excellent fluorescence, tunable emission, biocompatibility, aqueous solubility, surface functionalization ability, stability, safety, and cost-effectiveness. A growing number of studies explore the therapeutic, diagnostic, or theranostic use of CDs for ocular applications, demonstrating real-time monitoring of disease progression and treatment efficacy in ocular disease models. CDs have been explored for ocular drug delivery, fluorescent angiography, ocular bioimaging, and treatment in models of various ocular diseases, including bacterial keratitis, glaucoma, vitreous opacification, and neovascular age-related macular degeneration (nAMD). In this special report, the potential of CDs for ophthalmic applications is reviewed based on publications over the last decade.
Small interfering RNA (siRNA) therapeutics has huge potential for treating many diseases, including those incurable or undruggable by small molecules or antibodies, by harnessing RNA interference (RNAi) to achieve specific silencing of disease-associated genes. To date, all approved siRNA drugs are limited to liver targeting, largely due to delivery challenges. The two siRNA delivery platforms used clinically, namely lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc)-conjugation, are optimized for liver accumulation, restricting broader tissue targeting. Peptides offer a versatile approach to enhance siRNA delivery efficiency by functionalizing nanoparticles as surface ligands to enable specific cell targeting, facilitating cellular uptake and promoting endosomal escape. Alternatively, they can be used as standalone delivery system through complexation or covalent conjugation with siRNA while still fulfilling these roles. Over the years, the development of peptide-based siRNA delivery system has evolved from naturally occurring sequences, rational design, to phage display screening, with emerging machine-learning (ML) approaches expected to accelerate the discovery of novel peptides. This special report highlights the development of peptide-based delivery systems and discusses future directions toward next-generation siRNA delivery platforms to facilitate their successful clinical translation.
AIMS:To develop and evaluate a Quality-by-Design (QbD) optimized curcumin-loaded niosomal (OptCUR-NS) formulation for intranasal delivery and determine its delivery performance and in vitro activity against neuroblastoma. MATERIALS AND METHODS:A D-optimal design was used to optimize the Span 60:cholesterol ratio, Span 60:dicetyl phosphate ratio, and curcumin concentration. OptCUR-NS was characterized for vesicle properties, solid-state behavior, release, ex vivo nasal permeation, endothelial transport, cytotoxicity in SK-N-SH and SH-SY5Y cells, cellular uptake, cell-cycle distribution, migration, and cytocompatibility in F-180 fibroblasts. RESULTS:OptCUR-NS showed a particle size of 133.57 nm, surface charge of -48.16 mV, and entrapment efficiency of 62.05%. It exhibited biphasic release and increased nasal flux by 56% relative to free curcumin. Endothelial transport increased 1.57-fold without a significant change in transendothelial electrical resistance. In SK-N-SH cells, IC50 decreased from 78.94 to 69.67 µM at 24 h and from 70.54 to 50.24 µM at 48 h. Similar enhancement was observed in SH-SY5Y cells. Uptake was predominantly clathrin-dependent, accompanied by S-phase accumulation and reduced cell migration. CONCLUSIONS:OptCUR-NS improved curcumin permeation, endothelial transport, cellular uptake, and in vitro anti-neuroblastoma activity while maintaining fibroblast cytocompatibility and endothelial monolayer integrity under the conditions tested.
Nanotheranostics integrate diagnostic and therapeutic functions within nanoscale platforms and have emerged as promising tools for precision oncology by enabling image-guided drug delivery, real-time biodistribution tracking, treatment monitoring, and improved patient stratification. Despite substantial preclinical advances, few integrated nanotheranostic systems have achieved routine clinical implementation. This narrative review critically examines the translational barriers limiting the clinical adoption of oncology nanotheranostics, emphasizing manufacturing reproducibility, biological delivery, safety, clinical validation, and regulatory uncertainty. A structured literature search was conducted across PubMed, Scopus, Web of Science, ClinicalTrials.gov, U.S. Food and Drug Administration resources, European Medicines Agency resources, and relevant regulatory websites for evidence published between 2015 and 2026. Peer-reviewed studies, regulatory guidance documents, and authoritative institutional reports were prioritized, with evidence synthesized according to SANRA principles and PRISMA transparency guidelines. The review shows that clinical translation is constrained more by misalignment between technology development and clinical and regulatory requirements than by lack of innovation. Major challenges include batch-to-batch variability, limited Good Manufacturing Practice scalability, instability of multifunctional nanoparticle constructs, inconsistent tumor delivery, poor predictability of animal models, immunogenicity, protein corona formation, long-term safety concerns, and complex combination-product regulatory pathways. The review proposes a decision-oriented translational framework that prioritizes clinically actionable diagnostics, quality-by-design manufacturing, standardized characterization, human-relevant preclinical models, validated imaging endpoints, and early regulatory engagement. Aligning nanotheranostic development with clinical needs, manufacturing feasibility, and regulatory expectations is essential to accelerate successful translation into routine oncology practice.
BACKGROUND:Glioblastoma remains one of the most lethal brain malignancies due to its profound molecular heterogeneity, invasive biology, and poor drug penetration across the BBB. Clinically, USP7 is highly overexpressed and contributes to tumor aggressiveness in glioma. METHODS:Native USP7 inhibitors (P22077 and P5091) exhibit potent cytotoxicity but suffer from poor solubility, suboptimal pharmacokinetics, and limited BBB permeability, restricting their translational potential. To overcome these limitations, we developed PLGA-based nanoparticles of both inhibitors (nP22077 and nP5091) and observed efficient encapsulation with better pharmacokinetic profiles. RESULTS:Nano-encapsulation enhanced anti-glioma potency by ~10-fold, with nP5091 showing superior P53 restoration, MDM2 suppression, DNA damage induction, and apoptosis across in vitro, in vivo, and ex vivo assays. In subcutaneous xenografts and a stringent stereotactic orthotopic glioma model, nP5091 achieved substantial tumor regression, minimal systemic toxicity, and significantly prolonged survival, supported by strong molecular evidence of P53 reactivation and apoptotic signaling. CONCLUSION:Collectively, this work establishes nano-enabled delivery of USP7 inhibitors as a robust, mechanistically driven therapeutic strategy capable of overcoming key pharmacological barriers and offering a promising avenue for future glioma treatment.
The dysregulation of the gut-brain axis affects cerebral function, contributing to the occurrence of neuropsychiatric symptoms and the worsening of neurodegenerative disorders. The main and direct nerve connection between the gut and the brain is the gastrointestinal vagus nerve, which is activated by pathogenic bacteria. In the course of inflammatory bowel diseases, microbial dysbiosis and intestinal inflammation compromise the epithelial barrier, leading to increased levels of circulating pro-inflammatory cytokines, which cross the blood-brain barrier and trigger neuroinflammation. Restoring microbiota balance and effective delivery of neuroactive metabolites to the brain is therefore expected to attenuate both neuroinflammation and neuropsychiatric symptoms. This article highlights some recent manuscripts that take advantage of nanomedical tools to achieve modulation of the gut-brain axis responses, thus developing promising therapies for inflammatory and neurodegenerative disorders.
AIM:Despite advances in global medicine, tuberculosis (TB) remains a leading cause of mortality worldwide. The current TB regime is hampered by prolonged treatment duration that frequently results in poor patient adherence and suboptimal clinical outcomes. Lipid-based nanocarriers have emerged as a promising solution to these hurdles, supported by positive preclinical findings. This systematic review critically evaluates the therapeutic efficacy of these platforms and analyzes the interplay between antibacterial activity, protocols, and physicochemical characteristics. METHODOLOGY:Following a comprehensive search across four databases, 5,746 studies were identified up to February 2026. Data were extracted and reviewed using predetermined criteria via Rayyan software. RESULTS:Lipid-based nanocarriers significantly enhanced antibacterial activity, with minimum inhibitory concentration reduced up to approximately four-fold for conventional drug and 52-fold for experimental compounds. In vivo analysis revealed that drug-loaded solid lipid nanoparticles exhibited five-fold higher efficiency in clearing the bacterial burden in lungs and spleen as compared to oral free drugs. CONCLUSION:Lipid-based nanoparticles loaded with anti-TB drugs exhibited enhanced antibacterial efficacy in majority of the pre-clinical studies. Further standardization in methodology is required to support clinical translation. PROTOCOL REGISTRATION:www.crd.york.ac.uk/prospero identifier is CRD420251007329.
Myelosuppression induced by chemotherapy represents a critical bottleneck for patients with hematological malignancies, leading to a series of severe complications responsible for chemotherapy dose reduction, interruptions, and even treatment-related death. There exists an urgent need for strategies to repair the bone marrow microenvironment and thus promote early recovery from myelosuppression. Umbilical cord-derived mesenchymal stem cell exosomes (UCMSC-Exo), as the key effector of stem cells, exhibit multi-target characteristics, making them a promising candidate for bone marrow structural reconstruction and functional remodeling. This study is a single-arm, open-label, dose-escalation, single-center, phase I clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of UCMSC-Exo in the treatment of chemotherapy-induced myelosuppression in patients with acute myeloid leukemia. Nine to eighteen eligible participants will be enrolled sequentially into three UCMSC-Exo dose-escalation groups to receive a single infusion, after which they will be followed up for 12 months. The primary endpoints focus on safety and tolerability. Secondary endpoints include parameters assessing myelosuppression recovery, the incidence of myelosuppression-related complications, and supportive care. The study protocol has been approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.Clinical trial registration: NCT06245746.
