Gengshen Song

Introduction: Alzheimer’s disease (AD) imposes a significant global healthcare burden, and current available pharmacotherapies provide limited therapeutic benefits. Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment. Methods: Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil. The APP/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments. Results: In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced π‐π stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments. Pathological examinations revealed improved hippocampal morphology, upregulated neprilysin (NEP) expression, and reduced Aβ accumulation. The decreased malondialdehyde (MDA) levels further suggested a potential attenuation of systemic oxidative stress and provided preliminary support for further investigation into its effects on central redox status. Conclusion: These findings offer an initial phenotypic characterization of AC in an AD mouse model, underscoring the need for comprehensive mechanistic studies to fully evaluate its potential as a repurposed AD therapeutic candidate.

Lipid nanoparticle (LNP)‐mRNA technology has profoundly transformed the biomedical landscape, establishing itself as a highly versatile and powerful platform with substantial therapeutic and prophylactic potential across a wide range of diseases. This review summarizes recent advances in LNP delivery systems aimed at unlocking the full potential of RNA therapeutics. Key focuses include: 1) the design and screening of novel lipid molecules to improve mRNA delivery efficiency and targeting; 2) optimization of administration routes, LNP surface functionalization, and formulation components; and 3) advances in lyophilized LNP formulations. We also highlight the growing integration of artificial intelligence (AI) for designing next‐generation LNPs and overcoming existing translational barriers. Furthermore, the review provides a comprehensive overview of clinical applications of RNA‐LNPs in infectious diseases, cancer immunotherapy, gene therapy, cell‐based therapeutics, and RNAi‐LNP therapeutics, offering systematic strategies to enhance delivery efficacy and translational capacity. Finally, we discuss the future directions and unresolved challenges, including multimodal fusion delivery methodology of LNP and non‐LNP carriers, the interdisciplinary integration of various fields, and the bottleneck of extrahepatic delivery strategies, offering systematic insights into the translational pathway of mRNA‐LNP therapeutics.

Herpes zoster (HZ), caused by varicella zoster virus (VZV) reactivation commonly in elderly/immuno‐compromised individuals, leads to tremendous social burden. Despite approved vaccines, there is an urgent need for longer‐lasting and more effective HZ vaccines. This study designs a novel mRNA‐LNP vaccine targeting VZV glycoprotein E (gE), with the assistance of AI technology, achieving effective and enduring prevention against VZV infection with favorable safety. From numerous empirically designed antigen sequences, AI‐based screening identifies promising candidate variants, which are systematically evaluated based on their humoral and cellular immune responses in BALB/c mice. The study further explores the underlying correlation between the cellular localization and immunogenicity of the vaccine candidates and screens 5’UTR elements affecting mRNA expression. A 4‐week administration interval and immunogenicity are subsequently validated via detection of gE‐specific IgG antibodies and CD4 ⁺ T‐cell responses in mice. Notably, the vaccine VZV‐gEmD elicits strong humoral response, including gE‐specific IgG antibodies and VZV‐specific antibodies in rhesus macaques. The CD4 ⁺ T‐cell responses, critical for VZV reactivation protection, are significantly stronger and longer lasting with VZV‐gEmD than with Shingrix. These findings highlight its potential as an effective prophylactic vaccine for HZ and provide confidence for the utilization of this mRNA platform in VZV vaccine development.

Current therapeutics for chronic hepatitis B virus (HBV) infection are insufficient due to immune exhaustion caused by high circulating hepatitis B surface antigen (HBsAg) levels. Here, an HBV S region-targeted small interfering RNA (siRNA) is reported, aiming to dramatically suppress HBsAg and provide windows for host immune restoration. This siRNA agent, called KC13-M2G2, exhibits potent antiviral efficacy against all HBV genotypes in vitro. Notably, in multiple mouse models, KC13-M2G2 triggers rapid and sustained loss of HBsAg and HBV DNA accompanied by hepatitis B surface antibody seroconversion, outperforming the clinical drug elebsiran and bepirovirsen. Toxicity studies in Sprague-Dawley rats and cynomolgus monkeys indicate satisfactory biosafety profiles of KC13-M2G2. Given that elebsiran and bepirovirsen have achieved a functional cure rate of no more than 20% in their clinical studies, KC13-M2G2 as a more potent candidate drug is expected to exhibit superior performance in clinical applications.

Messenger RNA (mRNA) therapeutics have shown considerable promise across a wide range of medical applications with lipid nanoparticles (LNPs) emerging as the most clinically advanced mRNA delivery vehicles. However, the risk of off-target tissue delivery remains a concern, underscoring the need for diverse ionizable lipids to optimize LNP-based delivery systems. In this study, we designed and synthesized a library of 21 novel ionizable lipids and evaluated their potential for mRNA delivery. The resulting LNPs displayed favorable physicochemical properties and low cytotoxicity. In vitro transfection assay identified 3 high efficiency LNPs: YK-305, YK-310 and YK-319. In a mouse model, intramuscular injection of firefly luciferase (Fluc) mRNA-LNPs resulted in high transfection efficiency in muscle tissue, with significantly reduced gene expression in the liver. After encapsulating varicella zoster virus (VZV) glycoprotein E (gE)-encoding mRNA, the three LNP formulations induced robust humoral and cellular immune responses specific to the gE antigen, demonstrated improved selectivity and immunogenicity compared to SM-102, the ionizable lipid used in Moderna’s Spikevax. The safety of the gE-mRNA LNP formulations were subsequently demonstrated in a mouse model. Collectively, these findings provide a foundation for the optimization of tissue-targeting ionizable lipids and highlight their potential to advance mRNA-based vaccines in clinical applications. Graphical abstract