Bai Xiang

Background: The blood–brain barrier (BBB) and hydrolytic inactivation of the lactone form limit the efficacy of irinotecan (CPT-11) against glioma. To address these challenges, we developed a CPT-11-loaded hybrid liposome–U87MG cell membrane nanovesicle formulation (Hybrid/CPT-11), an underexplored biomimetic strategy for glioma therapy. This formulation combines the drug-loading and stabilizing capacity of liposomes (Lip) with the membrane-derived functionality of biomimetic nanovesicles (BNVs) prepared from U87MG cell membranes. Methods: Three preparation strategies—co-incubation, freeze–thaw followed by co-extrusion, and film hydration followed by co-extrusion—were compared. Membrane fusion was assessed by Förster resonance energy transfer (FRET) to select the optimal process. Physicochemical properties (TEM, hydrodynamic size/PDI, encapsulation efficiency, short-term storage and serum stability) were characterized. In vitro performance (U87MG uptake, 3D spheroid penetration, proliferation and migration inhibition) and in vivo biodistribution (Cy5 imaging), antitumor efficacy (bioluminescence imaging, tumor burden, survival), and biosafety (body weight, hematology, major-organ histology) were evaluated in orthotopic U87MG and U87MG-Luc glioma models. Results: Freeze–thaw followed by co-extrusion yielded the greatest FRET decrease and was selected. Hybrid/CPT-11 exhibited a uniform nanoscale size (178.4 ± 4.6 nm, PDI 0.22 ± 0.01), high encapsulation efficiency (61.6%), and stability. In vitro, Hybrid/Cou-6 showed enhanced cellular uptake and deeper penetration in 3D spheroids versus free Cou-6 and BNV/Cou-6. Hybrid/CPT-11 also exhibited the lowest IC₅₀ in U87MG cells compared with free CPT-11 and nonhybrid controls. In vivo, Hybrid/Cy5 prolonged systemic signal and enhanced brain accumulation versus Lip/Cy5 and BNV/Cy5. In orthotopic U87MG-Luc glioma, Hybrid/CPT-11 suppressed tumor bioluminescence, reduced endpoint tumor burden, and extended median survival (21 vs 16 days for free CPT-11), without significant weight loss, hematologic abnormalities, or major-organ pathology. Conclusion: This study developed a FRET-optimized hybrid liposome–U87MG cell membrane nanovesicle formulation that enhances brain delivery and therapeutic efficacy of irinotecan in orthotopic glioma.

Osteoarthritis (OA) is a debilitating degenerative joint disease urgently requiring disease-modifying therapies. Although multimodal RNA therapeutics (e.g., siRNA, miRNA, and mRNA) exhibit immense potential in reprogramming the complex OA pathological network, their clinical translation remains severely impeded by the hostile intra-articular microenvironment and rapid nucleolytic degradation. This review comprehensively evaluates the evolutionary trajectory of RNA delivery systems tailored for OA, advancing from conventional lipid nanoparticles (LNPs) and natural exosomes to sophisticated hierarchical platforms, including lipo-exosome hybrids, stimuli-responsive metal-organic frameworks (MOFs), and injectable hydrogels. These engineered vectors successfully breach cartilaginous barriers, enabling deep tissue penetration, prolonged joint retention, and microenvironment-responsive payload release. Finally, by synergizing advanced biomaterial engineering with precision genetic modulation, we outline the current translational bottlenecks and highlight future trajectories—such as the emerging role of artificial intelligence in rational nanocarrier design—to develop next-generation, dynamically responsive RNA therapeutics for authentic joint microenvironment remodeling.

Dry eye disease (DED), which affects over 30% of the global population, demands advanced therapeutic strategies to overcome ocular bioavailability challenges. We developed nanomicelles (RH40‐P188/RH40‐P407, CycloNex) for enhanced cyclosporine A (CsA) delivery through innovative biological validation platforms. The 15‐nm micelles demonstrated exceptional stability (3 months at 25°C) and deep tissue penetration (50 µm in 3D corneal spheroids), outperforming Cequa by 2.3‐fold in ex vivo rabbit corneal accumulation. A breakthrough microfluidic‐integrated 3D total corneal model revealed 82% prolonged ocular retention vs. Cequa, while our hyperosmotic cell platform showed 55% greater reactive oxygen species reduction and 44% lower TNF‐α expression. In vivo studies confirmed NM _P188 ‐CsA's superior bioavailability, and corneal repair was completed within 14 days in mice with benzalkonium chloride‐induced dry eye. These findings, validated through six complementary biological models—including HET‐CAM irritation scoring (0.89 vs. Cequa's 1.34)—establish a new paradigm for ocular nanotherapeutic evaluation while demonstrating clinically translatable advantages over current standards.

Oral insulin delivery is impeded by opposing surface-property requirements across sequential gastrointestinal barriers: hydrophilic/negatively charged interfaces are preferred for mucus penetration, whereas hydrophobic/positively charged surfaces favor epithelial uptake and transcytosis. We report the N-trimethyl chitosan-engineered sequential transporter (nanoNEST) system, a cost-effective hybrid nanoplatform comprising an insulin-loaded mesoporous carbon core carboxylated for stability and coated with trimethyl chitosan (TMC) grafted with a goblet cell-targeting CSK peptide. By tuning polymer coating to yield an overall negative zeta potential (~ -30 mV), the nanoparticles (NPs) rapidly traverse mucus while retaining epithelial interaction. CSK-mediated endocytosis promotes preferential Endoplasmic reticulum-Golgi apparatus (ER-Golgi) trafficking and basolateral exocytosis, and TMC enables reversible tight-junction opening for paracellular transport. In vitro, the NPs achieved a 10.05-fold higher apparent permeability across Caco-2 monolayers versus native insulin. In vivo, they exhibited prolonged GI retention and improved oral insulin bioavailability by 16.60-fold, eliciting sustained hypoglycemic effects. Repeated-dose safety studies showed favorable biocompatibility. This streamlined formulation integrates mucus penetration, targeted transcytosis, and transient junction modulation to overcome sequential barriers to oral biologics, highlighting its translational promise for scalable oral insulin delivery.

Leukemia is a highly heterogeneous and aggressive hematological malignancy. Current therapeutic approaches (e.g. chemotherapy, radiotherapy, small-molecule