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Background Malignant tumor is usually associated with epigenetic dysregulation, such as overexpression of histone deacetylase (HDAC), thus HDAC has emerged as a therapeutic target for cancer. Histone deacetylase inhibitor has been approved for clinical use to treat hematological cancers. However, the low solubility, short circulation lifetime, and high cytotoxicity partially limited their applications in solid tumor. Methods The upconversion nanoparticles (UC) modified with mesoporous silica (SUC) was used to load an HDACI, suberoylanilide hydroxamic acid (SAHA), and further camouflaged with M1 macrophage-derived exosome membranes (EMS). EMS was characterized in size and compositions. We also analyzed the epigenetic regulation induced by EMS. Furthermore, we evaluate the biodistribution and in vivo tumor inhibition after the systemic administration of EMS. Results This novel style spatiotemporal-resolved drug delivery system, EMS showed a high loading efficiency of SAHA. EMS could be taken up by lung cancer cells and lead to efficient epigenetic inhibition. We found that the integrin α4β1 on M1-EM, was crucial for the homing of EMS to tumor tissues for the first time. In tumor-bearing mice, EMS showed spatiotemporal-resolved properties and facilitated the drug accumulation in the tumors, which induced superior anti-tumor effects. Conclusion This novel style of spatiotemporal-resolved nanoparticles can be used as a theranostic platform for lung cancer therapy. Graphical Abstract

Pulmonary infection is a serious public health challenge with high morbidity and mortality. The employment of antibiotics is the first-line treatment for pulmonary infections, while other novel anti-infection agents, such as antimicrobial peptides, have also been developed due to the emergence of drug resistance. Recently, inhalable nanoparticle-based delivery systems have garnered significant attention for the delivery of anti-infection agents, which possess great advantages like high lung accumulations and precise delivery performances. However, the respiratory physiological structure, mucus and biofilm have been considered as the barriers that nanoparticle drug delivery systems facing, which compromise the therapeutic effects. In this integrative review, recent advances in the inhalable nanoparticle-based delivery system were introduced. In addition, we focused on the biological characteristics of these barriers and discussed effective strategies to overcome the obstacles, including precise deposition in the lower respiratory tract infection site, effective penetration of mucus and breaking of the biofilm barrier. To sum up, this review aimed to deepen the understanding of the fate of anti-infective nanoformulations in pulmonary delivery and find effective strategies to address the barriers, thus providing new insights for the development of pulmonary delivery systems against pulmonary infections.

Hepatocellular carcinoma (HCC) is a major global health issue, ranking as the sixth most common cancer and a leading cause of cancer-related deaths worldwide. Risk factors for HCC include chronic hepatitis B and C, obesity, alcohol abuse, diabetes, and metabolic disorders. Current treatments, such as surgery, transplantation, and chemotherapy, are often ineffective in advanced stages due to tumor resistance and the inability to target key oncogenic pathways. Recent advances in small interfering RNA (siRNA) therapy offer a promising solution to silence these pathways and hinder tumor progression. Nanoparticles, especially lipid-based nanoparticles (LNPs) like liposomes, solid lipid nanoparticles, exosomes etc. have emerged as an effective platform for siRNA delivery. LNPs provide critical advantages, including protection of siRNA from enzymatic degradation, improved cellular uptake, and precise tumor targeting through functionalization strategies. Compared to polymeric and metallic nanocarriers, LNPs demonstrate superior biocompatibility, biodegradability, and safety profiles. Furthermore, their ability to exploit natural mechanisms, such as apolipoprotein E (ApoE)-mediated uptake via low-density lipoprotein receptors on hepatocytes, enhances liver-specific delivery. This review explores advancements in siRNA therapeutics for HCC, highlighting nanoparticle-based delivery, cell signaling targets, and synthesis strategies. It also examines AI's role in optimizing siRNA design, formulation, and personalized treatment. These innovations enhance pathway-specific therapies, advancing clinical translation and improving HCC outcomes.

Background Insufficient solubility and stability of bioactive small molecules as well as poor biocompatibility may cause low bioavailability and are common obstacles in drug development. One example of such problematic molecules is 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE), a hydrophobic indirubin derivative. 6BIGOE potently modulates the release of inflammatory cytokines and lipid mediators from isolated human monocytes through inhibition of glycogen synthase kinase-3 in a favorable fashion. However, 6BIGOE suffers from poor solubility and short half-lives in biological aqueous environment and exerts cytotoxic effects in various mammalian cells. In order to overcome the poor water solubility, instability and cytotoxicity of 6BIGOE, we applied encapsulation into poly( d , l- lactide-co-glycolide) (PLGA)-based nanoparticles by employing formulation methods using the sustainable solvents Cyrene™ or 400 g/mol poly(ethylene glycol) as suitable technology for efficient drug delivery of 6BIGOE. Results For all preparation techniques the physicochemical characterization of 6BIGOE-loaded nanoparticles revealed comparable crystallinity, sizes of about 230 nm with low polydispersity, negative zeta potentials around − 15 to − 25 mV, and biphasic release profiles over up to 24 h. Nanoparticles with improved cellular uptake and the ability to mask cytotoxic effects of 6BIGOE were obtained as shown in human monocytes over 48 h as well as in a shell-less hen’s egg model. Intriguingly, encapsulation into these nanoparticles fully retains the anti-inflammatory properties of 6BIGOE, that is, favorable modulation of the release of inflammation-relevant cytokines and lipid mediators from human monocytes. Conclusions Our formulation method of PLGA-based nanoparticles by applying sustainable, non-toxic solvents is a feasible nanotechnology that circumvents the poor bioavailability and biocompatibility of the cargo 6BIGOE. This technology yields favorable drug delivery systems for efficient interference with inflammatory processes, with improved pharmacotherapeutic potential. Graphical Abstract

Background Esophageal cancer is the fifth most common cancer affecting men in China. The primary treatment options are surgery and traditional radio-chemotherapy; no effective targeted therapy exists yet. Self-assembled RNA nanocarriers are highly stable, easily functionally modified, and have weak off-tumor targeting effects. Thus, they are among the most preferred carriers for mediating the targeted delivery of anti-tumor drugs. miR-375 was found to be significantly down-regulated in esophageal squamous cell carcinoma (ESCC) tissues and its overexpression effectively inhibits the proliferation, migration, and invasion of ESCC cells. Moreover, epidermal growth factor receptor (EGFR) was overexpressed in ESCC cells, and accumulation of RNA nanoparticles in ESCC tumors was enhanced by EGFR-specific aptamer (EGFR apt ) modification. Results Herein, a novel four-way junction RNA nanocarrier, 4WJ-EGFR apt -miR-375-PTX simultaneously loaded with miR-375, PTX and decorated with EGFR apt , was developed. In vitro analysis demonstrated that 4WJ-EGFR apt -miR-375-PTX possesses strong thermal and pH stabilities. EGFR apt decoration facilitated tumor cell endocytosis and promoted deep penetration into 3D-ESCC spheroids. Xenograft mouse model for ESCC confirmed that 4WJ-EGFR apt -miR-375-PTX was selectively distributed in tumor sites via EGFR apt -mediating active targeting and targeted co-delivery of miR-375 and PTX exhibited more effective therapeutic efficacy with low systemic toxicity. Conclusion This strategy may provide a practical approach for targeted therapy of ESCC. Graphical Abstract

Nanoparticle-based drug delivery presents a promising solution in enhancing therapies for neurological diseases, particularly cognitive impairment. These nanoparticles address challenges related to the physicochemical profiles of drugs that hinder their delivery to the central nervous system (CNS). Benefits include improved solubility due to particle size reduction, enhanced drug penetration across the blood-brain barrier (BBB), and sustained release mechanisms suitable for long-term therapy. Successful application of nanoparticle delivery systems requires careful consideration of their characteristics tailored for CNS delivery, encompassing particle size and distribution, surface charge and morphology, loading capacity, and drug release kinetics. Literature review reveals three main types of nanoparticles developed for cognitive function enhancement: polymeric nanoparticles, lipid-based nanoparticles, and metallic or inorganic nanoparticles. Each type and its production methods possess distinct advantages and limitations. Further modifications such as coating agents or ligand conjugation have been explored to enhance their brain cell uptake. Evidence supporting their development shows improved efficacy outcomes, evidenced by enhanced cognitive function assessments, modulation of pro-oxidant markers, and anti-inflammatory activities. Despite these advancements, clinical trials validating the efficacy of nanoparticle systems in treating cognitive defects are lacking. Therefore, these findings underscore the need for researchers to expedite clinical testing to provide robust evidence of the potential of nanoparticle-based drug delivery systems.

Brain diseases are the most devastating problem among the world's increasingly aging population, and the number of patients with neurological diseases is expected to increase in the future. Although methods for delivering drugs to the brain have advanced significantly, none of these approaches provide satisfactory results for the treatment of brain diseases. This remains a challenge due to the unique anatomy and physiology of the brain, including tight regulation and limited access of substances across the blood-brain barrier. Nanoparticles are considered an ideal drug delivery system to hard-to-reach organs such as the brain. The development of new drugs and new nanomaterial-based brain treatments has opened various opportunities for scientists to develop brain-specific delivery systems that could improve treatment outcomes for patients with brain disorders such as Alzheimer's disease, Parkinson's disease, stroke and brain tumors. In this review, we discuss noteworthy literature that examines recent developments in brain-targeted nanomedicines used in the treatment of neurological diseases.

At present, the few photothermal/chemotherapy studies about retinoblastoma that have been reported are mainly restricted to ectopic models involving subcutaneous implantation. However, eyeball is unique physiological structure, the blood-retina barrier (BRB) hinders the absorption of drug molecules through the systemic route. Moreover, the abundant blood circulation in the fundus accelerates drug metabolism. To uphold the required drug concentration, patients must undergo frequent chemotherapy sessions. To address these challenges above, we need to develop a secure and effective drug delivery system (FA-PEG-PDA-DOX) for the fundus. We offered superior therapeutic efficacy with minimal or no side effects and successfully established orthotopic mouse models. We evaluated cellular uptake performance and targeting efficiency of FA-PEG-PDA-DOX nanosystem and assessed its synergistic antitumor effects in vitro and vivo. Biodistribution assessments were performed to determine the retention time and targeting efficiency of the NPs in vivo. Additionally, safety assessments were conducted. Cell endocytosis rates of the FA-PEG-PDA-DOX+Laser group became 5.23 times that of the DOX group and 2.28 times that of FA-PEG-PDA-DOX group without irradiation. The fluorescence signal of FA-PEG-PDA-DOX persisted for more than 120 hours at the tumor site. The number of tumor cells (17.2%) in the proliferative cycle decreased by 61.6% in the photothermal-chemotherapy group, in contrast to that of the saline control group (78.8%). FA-PEG-PDA-DOX nanoparticles(NPs) exhibited favorable biosafety and high biocompatibility. The dual functional targeted nanosystem, with the effects of DOX and mild-temperature elevation by irradiation, resulted in precise chemo/photothermal therapy in nude mice model.

This study aimed to develop a solid self-nanoemulsifying drug delivery system (SNEDDS) and surface-coated microspheres to improve the oral bioavailability of niclosamide. A solubility screening study showed that liquid SNEDDS, prepared using an optimized volume ratio of corn oil, Cremophor RH40, and Tween 80 (20:24:56), formed nanoemulsions with the smallest droplet size. Niclosamide was incorporated into this liquid SNEDDS and spray-dried with calcium silicate to produce solid SNEDDS. Surface-coated microspheres were prepared using sodium alginate and poloxamer 407 and optimized through solubility and dissolution tests. Scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction were used to evaluate the physicochemical properties of the prepared solid SNEDDS, surface-coated microspheres, and the drug alone. The solubility, dissolution, and oral bioavailability were also assessed. Physicochemical evaluation demonstrated that niclosamide was converted to an amorphous state in the Solid SNEDDS formulation, with enhanced solubility and oral bioavailability. In comparison to niclosamide alone, solid SNEDDS exhibited an increase in drug solubility (approximately 2500-fold vs 158-fold) and oral bioavailability (approximately 10-fold vs 1.65-fold), significantly outperforming surface-coated microspheres. This solid SNEDDS formulation may be an excellent candidate for niclosamide with improved oral bioavailability for repurposing.

In recent years, combination chemotherapy with therapeutic nucleic acids has emerged as a promising strategy to enhance the effectiveness of cancer therapy. However, developing an effective co-delivery system to simultaneously transport both chemotherapeutic drugs and nucleic acids remains challenging. Herein, we fabricated cholesterol-conjugated polyion complex nanoparticles (PCNs) for combination delivery of hydrophobic paclitaxel (PTX) and hydrophilic miR-34a. Cholesterol was conjugated to polyethylenimine (PEI) and hyaluronic acid (HA), producing C–PEI and C–HA, respectively. PTX was initially encapsulated within the hydrophobic core formed by the self-assembly of C–HA and C–PEI, yielding polyion complex nanoparticles (PTX@C–HA/C–PEI PCNs). Subsequently, the negatively charged miR-34a was electrostatically complexed with the cationic C–PEI moieties to generate miR-34a/PTX@C–HA/C–PEI PCNs. These PCNs exhibited a nanoscale structure with a uniform size distribution and demonstrated low cytotoxicity in colon cancer cells. Fluorescence microscopy confirmed efficient cytosolic delivery of C–HA/C–PEI PCNs in colon carcinoma cells. Furthermore, combination delivery of PTX and miR-34a using C–HA/C–PEI PCNs exhibited significantly enhanced transfection efficiency and cellular uptake for human colon cancer cells. Notably, PTX/miR-34a@C–HA/C–PEI PCNs effectively downregulated critical oncogenic targets, including Notch1, Snail1, and BCL-2, resulting in reduced cancer cell migration and proliferation. These findings indicate that PTX/miR-34a@C–HA/C–PEI PCNs hold significant potential as an innovative combination delivery platform, offering improved therapeutic efficacy for colon cancer therapy.