Fuqiang Hu

Background: Intestinal epithelial barrier disruption contributes to persistent inflammation in inflammatory bowel disease (IBD). CHIR99021 (CHIR) can promote epithelial regeneration and barrier repair, but its oral use is limited by premature gastric release and insufficient intestinal retention. This study aimed to develop an oral formulation that improves intestinal delivery of CHIR and supports barrier restoration. Methods: CHIR-loaded lipid nanoparticles (LNPs@CHIR) were prepared using glyceryl monostearate and Eudragit L100 and incorporated into a thiolated hyaluronic acid (HS) precursor to form HS/LNPs@CHIR (HSL@C). The system was characterized for particle size, mucoadhesion, and drug release, and its therapeutic effects were evaluated in IEC-6 cells and a mouse model of colitis. Results: LNP encapsulation reduced premature CHIR release under simulated gastric conditions, whereas the HS component enabled reactive oxygen species (ROS)-responsive gelation and ROS-scavenging activity. After oral administration, HSL@C exhibited prolonged colonic retention for up to 24 h. HSL@C promoted intestinal epithelial regeneration and barrier restoration while alleviating tissue injury and pro-inflammatory cytokine production. Conclusions: HSL@C integrates gastric protection, prolonged intestinal retention, ROS-responsive gelation, and epithelial regeneration within an oral delivery system, collectively supporting its potential as a promising barrier-restorative nanoparticle–hydrogel platform for the treatment of IBD.

Autophagy dysfunction is intimately involved in Alzheimer's disease (AD) pathogenesis, and restoring autophagy may alleviate pathology and improve cognition. Brain microvascular endothelial cells (BMECs) represent the primary source of acid sphingomyelinase (ASM), which inhibits neuronal autophagy. Suppressing ASM in BMECs can restore autophagy and potentially treat AD. To address this target, we developed a liposomal formulation (RVG-pSL@FIN/RSV) loaded with fingolimod (FIN) and rosuvastatin (RSV), and modified with rabies virus glycoprotein (RVG) peptide to target BMECs and neurons. Upon targeting BMECs, RVG-pSL@FIN/RSV releases FIN, which serves dual functions: inhibiting ASM production in BMECs and promoting transport across the blood-brain barrier (BBB). This transport enhancement facilitates subsequent passage of RVG-pSL@FIN/RSV across the BBB to target neurons, where FIN is released to inhibit both ASM and phosphorylated tau protein (p-Tau) production. Simultaneously, RSV is released within the neurons to restore autophagy, clearing accumulated p-Tau and amyloid-beta (Aβ) proteins while inhibiting Aβ aggregation. Our dual-targeting nanodelivery system modulates BMECs and neurons, inhibiting ASM activity while enhancing trans-BBB transport. RVG-pSL@FIN/RSV reduces BMEC-derived ASM in AD mice, restores autophagy, suppresses pathogenic protein accumulation, and improves cognition. This work presents a nanodelivery system targeting BMEC-derived ASM to restore autophagy as a potential therapeutic strategy for AD.

Ulcerative colitis (UC), a chronic inflammatory disorder of the colon, remains challenging to treat due to limited efficacy with current therapies. Ferroptosis, a newly identified form of programmed cell death, contributes significantly to UC pathogenesis and might offer promising therapeutic potential. Herein, we developed an oral synergistic regulation of ferroptosis using a solid lipid nanocomplex-embedded inulin gel (SLN/Que&OA@Gel) for colon-targeted UC therapy; solid lipid was utilized to encapsulate oleic acid (OA) and quercetin (Que) for better intestinal bioavailability, which was further embedded in an inulin gel to realize colon targeting. The system combines OA─which modulates lipid composition to reduce ferroptosis susceptibility─with Que, an antioxidant that scavenges reactive oxygen species (ROS) and suppresses oxidative stress to limit ferroptosis progression. Simultaneously, the incorporation of the inulin gel matrix ensures gastrointestinal tract protection, mucoadhesion, prolonged retention time at the lesion site, and sustained drug release, which promise a better curative effect. In vivo studies demonstrate that SLN/Que&OA@Gel effectively remodels the UC-associated pathological microenvironment by alleviating intestinal damage, restoring intestinal barrier integrity, and reducing inflammation. This strategy of synergistic regulation of ferroptosis and microenvironment remodeling presents a promising therapeutic avenue for UC management.

Schematic representation of the underlying therapeutic mechanism of Exo-124-3p for Alzheimer's disease combination therapy.

Ischemia-reperfusion (IR)-induced acute kidney injury (AKI) is a life-threatening form of AKI frequently observed in clinical settings, such as hemorrhagic shock, kidney transplantation, and cardiovascular surgery. Targeting renal antioxidant therapy may represent an effective strategy against IR-induced AKI. Bilirubin (BR), a specific superoxide anion scavenger, faces limitations in clinical application due to its poor water solubility and hepatic metabolism pathway. In this study, we prepared bilirubin nanocrystals (BRNCs), which demonstrated potent antioxidant effects in vitro experiments. To enhance renal targeting, BRNCs were encapsulated in poly(ethylene glycol) (PEG)-modified lipid nanoparticle (BRNC-LNP). In vivo distribution studies revealed that BRNC-LNP effectively circumvented hepatic metabolism and exhibited enhanced renal accumulation compared to BRNC. In vivo efficacy evaluation revealed superior therapeutic outcomes with BRNC-LNP versus BRNC in AKI mice. These findings suggest that BRNC-LNP may serve as a promising therapeutic strategy for IR-induced AKI by reducing the level of hepatic metabolism and promoting renal targeting.

Background/Objective: Staphylococcus aureus (S. aureus) is a clinically significant pathogenic bacterium. Daptomycin (DAP) is a cyclic lipopeptide antibiotic used to treat infections caused by multidrug-resistant Gram-positive bacteria, including S. aureus. However, DAP currently faces clinical limitations due to its short half-life, toxic side effects, and increasingly severe drug resistance issues. This study aimed to develop a biomimetic nano-drug delivery system to enhance targeting ability, prolong blood circulation, and mitigate resistance of DAP. Methods: DAP-loaded chitosan nanocomposite particles (DAP-CS) were prepared by electrostatic self-assembly. Macrophage membrane vesicles (MM) were prepared by fusion of M1-type macrophage membranes with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). A biomimetic nano-drug delivery system (DAP-CS@MM) was constructed by the coextrusion process of DAP-CS and MM. Key physicochemical parameters, including particle diameter, zeta potential, encapsulation efficiency, and membrane protein retention, were systematically characterized. In vitro immune escape studies and in vivo zebrafish infection models were employed to assess the ability of immune escape and antibacterial performance, respectively. Results: The particle size of DAP-CS@MM was 110.9 ± 13.72 nm, with zeta potential +11.90 ± 1.90 mV, and encapsulation efficiency 70.43 ± 1.29%. DAP-CS@MM retained macrophage membrane proteins, including functional TLR2 receptors. In vitro immune escape assays, DAP-CS@MM demonstrated significantly enhanced immune escape compared with DAP-CS (p < 0.05). In the zebrafish infection model, DAP-CS@MM showed superior antibacterial efficacy over both DAP and DAP-CS (p < 0.05). Conclusions: The DAP-CS@MM biomimetic nano-drug delivery system exhibits excellent immune evasion and antibacterial performance, offering a novel strategy to overcome the clinical limitations of DAP.