The Zika virus (ZIKV), a neurotropic flavivirus, poses a significant global health threat due to its association with severe congenital malformations. The absence of approved antivirals necessitates novel therapeutic approaches. Curcumin, a natural polyphenol from Curcuma longa, exhibits potent anti-inflammatory and broad-spectrum antiviral properties but is plagued by poor solubility and bioavailability. This study aimed to develop and comprehensively evaluate Curcumin-loaded Solid Lipid Nanoparticles (CUR-SLNs) to overcome these limitations. A 3[2] factorial design optimized SLNs using glyceryl monostearate. The lead formulation (CUR-SLN6) exhibited a particle size of 53.25 nm, a high entrapment efficiency of 93.2%, and sustained in vitro release (52.89% over 24 hours). In Wistar rats, CUR-SLNs demonstrated a 15-fold increase in oral bioavailability compared to native curcumin and significant brain biodistribution. In a Vero cell-based antiviral assay, CUR-SLNs exhibited a 90% reduction in ZIKV plaque formation (IC50 = 2.5 µM), ten times more potent than native curcumin. Histopathological analysis in a lethal AG129 mouse model showed that CUR-SLN6 treatment provided marked protection against ZIKV-induced neuronal necrosis and inflammation, with efficacy comparable to Sofosbuvir. No systemic toxicity was observed. Stability studies confirmed the formulation's robustness. This study is the first to demonstrate that SLN-based delivery of curcumin not only enhances its bioavailability and brain targeting but also provides neuroprotective efficacy against ZIKV infection comparable to a direct-acting antiviral, highlighting its clinical potential as an oral neurotherapeutic agent.

Periodontitis is a chronic oral inflammatory disease commonly caused by bacterial infection that affects oral health. Ciprofloxacin (CIP) is an antimicrobial agent with low water solubility (0.067 mg/mL at 25 °C, pH 7.5) and poor permeability. This research aims at fabricating chitosan/gellan gum hybrid extended release in-situ forming implants (CG-IFIs) loaded with CIP/Poloxamer 407 solid dispersion for treatment of periodontitis. Solid dispersions were loaded into chitosan/gellan gum matrix, cross linked with 2% w/v sodium bicarbonate. Upon exposing the implants to body temperature, a sol-gel transition occurs. The implants were evaluated for gelation time, injectability, in-vitro drug release, surface morphology and erosion rate. Results indicated that formulation (CG-IFI3) comprising 1% (w/v) chitosan, 0.2% (w/v) gellan gum, and a 2:1 w/w ratio of Poloxamer 407/CIP solid dispersion exhibited an appropriate gelation time (12 ± 2.5 min), favorable flow rate (0.83 ± 0.05 ml/min), and sustained drug release over two weeks. The selected formulation (CG-IFI3) was injected intragingivally into the mandibular incisive region of a rat model after induction of periodontitis via the ligature method. After 15 days of treatment, CG-IFI3 significantly reduced periodontal inflammation, vascular congestion, and tissue infiltration. These findings suggest that CG-IFI3 is a promising localized delivery system for managing periodontitis.

Despite the increasing utilisation of radiotherapy in the clinical management of hepatocellular carcinoma (HCC), therapeutic efficacy is frequently compromised by radioresistance, which leads to local recurrence and metastasis. Improving the radiosensitivity of HCC cells has therefore become a key focus of current research. Interleukin-21 (IL-21) is a pleiotropic immune regulator known to induce the proliferation of tumour antigen-specific T cells, enhance NK cell cytotoxicity, and modulate the immune microenvironment. However, its role in the context of radiotherapy for HCC remains unclear. In this study, we investigated the anti-tumour effect of IL-21 combined with radiotherapy in HCC-bearing mouse models. We found that treatment with an attenuated Salmonella strain engineered to deliver an IL-21 expression plasmid, in combination with radiotherapy, effectively restored IL-21 levels within tumour tissues of HCC-bearing mice. This combination therapy significantly inhibited tumour growth, promoted tumour cell apoptosis, elevated the ratios of T lymphocytes and NK cells in the spleen, and enhanced lymphocyte infiltration and activation within the tumour microenvironment. Collectively, our findings demonstrate that attenuated Salmonella carrying an IL-21 expression plasmid effectively potentiates the anti-tumour efficacy of radiotherapy by enhancing systemic anti-tumour immune responses, providing a novel combinatorial strategy for improving radiotherapeutic outcomes in HCC patients.

Piperine, derived from black pepper, exhibits powerful cardioprotective activity. However, its poor solubility limits its clinical translation for myocardial infarction (MI) management. This study aims to develop piperine-loaded lipopolymersomes for MI, to assess systemic and cardiac exposure. Lipopolymersomes were prepared using emulsification-solvent evaporation method, followed by surface coating with TPGS. The lipid-to-polymer ratio and nanoparticles-to-drug ratio were optimised for ideal particle size, zeta potential, and encapsulation efficiency. Oral pharmacokinetics and physiologically based pharmacokinetic (PBPK) modelling were conducted to evaluate bioavailability enhancement and predict cardiac exposure. Cardioprotective efficacy was assessed using an isoprenaline-induced mouse model of MI. TPGS-decorated lipoloymerosomes (O1-TPGS) exhibited a size of 188.56 ± 8.33 nm, a zeta potential of -19.67 ± 2.81 mV, and 98.67 ± 4.80%. entrapment efficiency. The formulation provided sustained piperine release over 72 h. Piperine oral systemic exposure was increased by 1.5-fold. PBPK simulation predicted a three-fold increase in cardiac concentration and area under the curve for O1-TPGS versus unformulated piperine. O1-TPGS normalised heart rate, reduced creatinine kinase-MB and troponin-I, and suppressed NLRP3, mTOR, NF-κB, and IL-6 than standard piperine, with superior preservation of myocardial architecture. TPGS-modified lipopolymersomes markedly enhanced the systemic and cardiac bioavailability of piperine, translating this pharmacokinetic improvement into superior cardioprotective effects in isoprenaline-induced MI.

Cancer therapy demands smarter, more targeted strategies that minimise healthy tissue damage while maximising therapeutic efficacy. This study introduces Hy-Si-IONC, a dual heat- and pH-responsive hydrogel-coated magnetic nanocluster, engineered to deliver chemotherapeutic drug within the tumour microenvironment. When combined with magnetic hyperthermia, it offers targeted, localised drug release, outperforming conventional single-stimulus carriers. The encapsulation efficiency and drug loading capacity of the Hy-Si-IONC were 47.3% and 4.6%, respectively. Hy-Si-IONC exhibited a lower critical solution temperature (LCST) of 43 °C with drug-release potential of 41.89% under tumour-mimicking conditions. A combinational therapy of doxorubicin-loaded Hy-Si-IONC and magnetic hyperthermia reduced the cell viability to 18% in MDA-MB-231 cells, confirming a strong therapeutic effect between thermal and chemotherapy. The nanosystem displayed good compatibility with human lymphocytes, MCF-7 and MDA-MB-231 cell lines. Haemolysis remained below 1%, and no genotoxicity was detected. Long-term in vivo safety was confirmed in a 25-week mice study; the nanoclusters predominantly accumulated in the liver and spleen. Transient changes in antioxidant markers - superoxide dismutase (SOD), catalase, glutathione S-transferase (GST), and glutathione (GSH) normalised by the end of the study. No major histopathological abnormalities were observed in vital organs. Collectively, Hy-Si-IONC presents a biocompatible and potential dual-modal cancer therapy.

The therapeutic potential of tectoridin for melasma treatment is limited by its poor aqueous solubility. To address this limitation, we developed tectoridin-loaded ethosomes using the film dispersion method, and optimised the formulation via orthogonal design, before incorporation of these ethosomes into a gel. The optimised tectoridin ethosomes showed a spherical morphology with uniform dispersion, a particle size of 197.84 ± 1.43 nm, a zeta potential of -22.75 ± 0.61 mV, a polydispersity index of 0.209 ± 0.05, an encapsulation efficiency of 92.82 ± 0.16%, and a drug loading of 9.75 ± 0.05%, thereby demonstrating good storage stability for 30 days at both 4 °C and 25 °C. The resulting Tectoridin (Te)-Ethosomes-Loaded Thermosensitive Gel (Te-ethosomes@Gel) exhibited suitable rheological properties, erosion rate and in vitro release profile. Both ethosomes and the gel enhanced drug release, cellular uptake and safety. All tectoridin formulations significantly inhibited tyrosinase activity, reduced melanin content and deposition in PIG1 cells and suppressed the expression of transcription of tyrosinase, TRP1, MITF, Myosin Va, Rab27a, Cdc42, p-p38 and p-ERK proteins. In vivo pharmacodynamic studies in a rat model of melasma further demonstrated that the Te-ethosomes@Gel significantly improved skin pigmentation, reduced oxidative stress markers and restored normal skin histology, with effects superior to those of free tectoridin or ethosomes alone. These findings demonstrate that Te-ethosomes@Gel offers a promising novel strategy for treating melasma.

Acute liver injury (ALI) is a syndrome characterised by rapid deterioration of liver function, rapid progression, and high mortality. In this study, a liver-targeted drug delivery system, galactosylated chitosan modified Coreopsis tinctoria flavonoid liposome (GC-CTF-Lip) was constructed. The targeted ligand was synthesised by the amidation reaction between chitosan and lactobionic acid, and its structure was identified. The modification conditions of GC on liposomes were optimised and characterisation of liposomes was studied. The liver-targeting ability of GC-CTF-Lip was evaluated through in vivo and in vitro experiments. A mouse model of ALI induced by CCl4 was established to evaluate the hepatoprotective effect of GC-CTF-Lip. The results confirmed that lactobionic acid was successfully grafted onto chitosan. Finally, GC-CTF-Lip with particle size of 236.32 ± 0.60 nm and encapsulation efficiency of 68.67 ± 0.58% was obtained. GC-CTF-Lip improved the uptake efficiency of CTF in hepatocytes in vitro and exhibited excellent liver enrichment in vivo. Serum ALT/AST levels were significantly decreased, and the histological liver injury was alleviated. It exhibited a trend of liver enrichment and a hepatoprotective effect. This liver-targeted nanodrug delivery system can achieve active accumulation of drugs at the lesion site, providing a potential strategy for the prevention of ALI.

Drug repurposing can accelerate oncology translation by leveraging approved compounds with known pharmacology; success depends on a plausible mechanism for the new indication. The microtubule cytoskeleton is a validated anticancer target, yet tubulin-directed activity is often overlooked for non-oncology drugs. Using nanoDSF, FDA-approved compounds were recently screened for effects on tubulin polymerisation, identifying multiple previously unrecognised microtubule-targeting agents (MTA) including Auranofin, Ebselen, Riboflavin, Aprepitant, Benzarone and Nifedipine derivatives, etc. Many hits match reported microtubule perturbation or cancer-relevant phenotypes, and several have been considered for oncology repositioning. These observations suggest microtubule targeting may contribute to anticancer effects more often than appreciated and that tubulin remains an underexploited repurposing target. The aim of this review is to place these newly identified MTAs in the context of current knowledge and to discuss their potential for drug repurposing in oncology.

Conventional ulcerative colitis (UC) therapies suffer from limited efficacy and toxicity. Although physcion (PHY) has multi-target anti-inflammatory activity, its poor solubility and lack of targeting restrict clinical use. To overcome these issues, we developed folate receptor (FR)-targeted DSPE-PEG liposomes encapsulating PHY using thin-film hydration and central composite design optimization. The resulting liposomes showed uniform size (approximately 160 nm, PDI < 0.18), high entrapment efficiency (>92%), and good stability. In vitro release was significantly improved, and cellular uptake was enhanced in inflammatory EC cells via FR-mediated endocytosis. Pharmacokinetic studies revealed prolonged half-life and increased bioavailability, while tissue distribution confirmed colon-specific enrichment. In DSS-induced UC mice, targeted liposomes repaired colonic mucosa, reduced fibrosis, suppressed pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and alleviated oxidative stress through coordinated NF-κB/Nrf2 regulation, with efficacy superior to conventional liposomes and positive controls. Safety assessments showed no notable cytotoxicity to normal cells. This work offers a promising FR-targeted nanocarrier to overcome PHY's clinical limitations and provides a foundation for targeted UC therapy.

Breast cancer remains one of the most prevalent causes of cancer deaths globally. This is because systemic toxicity, multidrug resistance and poor tumour selectivity typically make treatment less effective. Traditional drug delivery methods depend heavily on passive targeting and diffusion-controlled release. Enzyme-responsive drug delivery systems have recently been developed as a biologically precise approach that takes clinical advantage of the specialised enzymatic environment of breast tumours, such as the overproduction of matrix metalloproteinases, cathepsins and hyaluronidase. Among advanced nanocarriers, two-dimensional (2D) nanomaterials have attracted significant attention because of their high surface-to-volume ratio, ultrathin planar structure, tuneable surface chemistry, and exceptional drug-loading capacity. Graphene derivatives, black phosphorus, layered double hydroxides, transition metal dichalcogenides, and MXenes are all examples of materials that can be used to make enzyme-cleavable linkers. This paper critically discusses the enzymatic characteristics of the breast tumour microenvironment, design principles of enzyme-responsive linkers, classifications and physicochemical properties of 2D nanomaterials and their functionalization strategies. Furthermore, toxicity considerations, preclinical advancements, translational barriers, and future perspectives are analysed. Collectively, enzyme-responsive 2D nanomaterials represent a promising next-generation approach for precision breast cancer therapy, offering improved targeting efficiency, controlled drug activation, and potential theranostic integration.

Molecular engineering, chemical biology and translational oncology have transformed the landscape of targeted cancer therapies. Antibody-drug conjugates (ADCs) have advanced into clinically validated platforms that combine antigen-specific recognition with potent cytotoxic payloads, supported by innovations in linker chemistry, drug-to-antibody ratio (DAR) optimisation, and bispecific or multispecific antigen targeting. Parallel to ADC development, targeted protein degradation (TPD) technologies - proteolysis-targeting chimaeras (PROTACs), molecular glues, and emerging lysosomal and autophagy-based degraders enable the catalytic elimination of oncogenic drivers that were previously considered undruggable. Nanomedicine-based delivery enhances therapeutic selectivity, improves pharmacokinetics and overcomes barriers to intracellular drug transport. Rational combination therapies that integrate these platforms with immune checkpoint inhibitors, kinase inhibitors and tumour microenvironment (TME)-modulating agents address tumour heterogeneity and adaptive resistance more effectively than monotherapies. This review synthesises the foundations of ADCs, multispecific antibodies, protein degraders, nanomedicine platforms, targeted small-molecule inhibitors and their combination strategies. Clinically, the convergence of these modalities promises to extend durable responses to patient populations with refractory, molecularly complex malignancies by enabling individualised, mechanism-driven therapeutic selection.

Subcellular organelle targeting is changing the way nanomedicine is designed, moving the field beyond simple cellular entry towards more precise intracellular localization, controlled cargo release, and functional activity within disease-relevant compartments. This review critically discusses nanomaterial-based strategies for targeting the nucleus, mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus, and cytoskeleton-associated trafficking pathways. Its main novelty is the use of a cross-organelle, mechanism-based framework that links nanocarrier physicochemical properties with intracellular transport biology, rather than examining each organelle or delivery platform separately. Nanocarriers are compared according to their targeting mechanisms, cargo compatibility, therapeutic potential, and translational limitations. Particular attention is given to nuclear import mediated by NLS-, CPP/TAT-, and aptamer-based strategies; mitochondrial delivery shaped by membrane potential, membrane fusion, and redox-responsive release; lysosomal targeting for pH- and enzyme-activated therapies; and ER/Golgi-directed delivery through retrograde trafficking, retention motifs, and modulation of stress-related pathways. The review also focus on stimuli-responsive release, biomimetic surface engineering, extracellular vesicle scalability, CRISPR/Cas delivery, base and prime editing, and targeted protein degradation, all of which may support more programmable forms of intracellular therapy. Importantly, it separates true organelle localisation from transient trafficking or non-specific perinuclear accumulation, emphasising the need for stronger and more reliable validation methods.

Eletriptan hydrobromide (EHBr) exhibits poor oral bioavailability due to extensive first-pass metabolism by CYP3A4 and P-glycoprotein-mediated efflux at the blood-brain barrier. Therefore, this study was conceptualised to encapsulate EHBr into solid lipid nanoparticles (SLNs) and deliver them via a transdermal microneedle (MN) array for targeted brain delivery. SLNs were formulated using a lipid matrix comprising glyceryl monostearate, stearic acid and hydrogenated soy phosphatidylcholine, with Poloxamer-188 as the emulsifier. The optimised SLNs showed a particle size of 165.5 ± 71.75 nm, zeta potential of -27.1 ± 4.48 mV and entrapment efficiency of 63.25 ± 1.44%, and were incorporated into polymer-based MNs. The optimised MNs exhibited high drug content (93.65 ± 1.39%), good mechanical strength (p < 0.05), excellent insertion efficiency (F = 17.83, p = 3.03 × 10[-8]) and rapid in situ dissolution. Ex vivo studies demonstrated sustained EHBr release (89.67 ± 1.03% over 24 h), following first-order kinetics (R[2] = 0.998) with non-Fickian diffusion (n = 0.79). FTIR and XRD analyses confirmed drug excipient compatibility and formulation stability. In vivo evaluation in Wistar rats revealed significant antinociceptive, anxiolytic and anti-photophobic effects (p ≤ 0.027), and reduced neurogenic inflammation, confirming the enhanced brain delivery and bioavailability of EHBr.

Gastrointestinal (GI) malignancies are leading causes of global cancer mortality, with advanced stages showing pronounced therapeutic resistance. A key driver of this aggression is the immunosuppressive and acidic tumour microenvironment (TME). This niche is critically regulated by hypoxia-inducible carbonic anhydrase (CA) isoforms IX and XII. These enzymes catalyse extracellular carbon dioxide hydration, acidifying the milieu to promote invasion, metastasis and immune evasion. Pharmacological CA IX/XII inhibition counteracts this by normalising pH, reducing invasiveness and reinvigorating anti-tumour immunity. Oncolytic viruses (OVs) represent a complementary immunotherapeutic modality. Engineered to selectively replicate in tumour cells, OVs induce direct cytolysis and immunogenic cell death, thereby stimulating systemic immunity. However, their efficacy is hindered by the very acidosis sustained by CA activity. This establishes a compelling synergy: CA inhibition alleviates the acidic barrier to enhance OV spread and potency. Conversely, OV-mediated lysis disrupts hypoxic tumour regions, subsequently downregulating CA IX/XII expression and mitigating acidification. This bidirectional, self-reinforcing cycle positions their combination as a rational strategy to dismantle the TME's metabolic and immunological defences. Preclinical evidence supports that this multimodal approach enhances tumour regression, suppresses metastasis and prolongs survival, offering a promising translational paradigm for GI cancers.

The present study aimed to develop and comprehensively evaluate dalfampridine-loaded chitosan nanoparticles (DLM-CSNPs) for enhanced intranasal brain delivery in a cuprizone-induced demyelination model of multiple sclerosis (MS). The optimised nanoparticles were found to have a particle size of 166.5 nm with PDI 0.24, a positive surface charge (Zeta Potential +24.97 mV), and high entrapment efficiency (82%). Ex Vivo Permeation studies demonstrated that the permeation rate of the drug from DLM-CSNPs (902.26 µg/cm[2]) was significantly higher compared to the drug solution (609.96 µg/cm[2]). Sub-acute toxicity studies indicated the lack of significant systemic, hepatic, and renal toxicity of the compound after 28 days of repeated intranasal administration, even at a dose of 4 mg/kg. Pharmacokinetic studies indicated the better targeting of the brain by the intranasal route, where the brain Cmax was two-fold higher, brain AUC 0-12 was significantly higher, brain Tmax was significantly lower, and the brain/plasma ratios were significantly higher compared to the oral route. When compared to the traditional oral route of administration, the intranasal DLM-CSNPs treatment has demonstrated improved delivery of the formulation to the central nervous system, functional recovery, decreased neuroinflammation, and neuroprotective effects, suggesting the therapeutic potential of the DLM-CSNPs formulation for the management of multiple sclerosis.