Zong Xinyu, Xiao Shangying, Xia Haishan, Guo Dan, Wu Jiaping, Zhuang Manjiao, Rao Lei
Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Medical College, Shaoguan University, Shaoguan, 512005, People's Republic of China.
School of Pharmacy, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China.
Drug Des Devel Ther. 2025 Apr 22;19:3103-3118. doi: 10.2147/DDDT.S499641. eCollection 2025.
BAY55-9837, a potential therapeutic peptide for the treatment of type 2 diabetes mellitus (T2DM), can induce glucose (GLC)-dependent insulin secretion. Our previous study has demonstrated that the use of superparamagnetic iron oxide nanoparticle-decorated exosome (exosome-SPION) and external magnetic force (MF) enables BAY 55-9837 to target pancreatic islets. However, the initial burst release of BAY 55-9837 loaded within exosome-SPION shortens its in vivo half-life and consequently reduces the frequency of GLC responsiveness. Therefore, in our study, the transmembrane hydrophobic structure of the exosome signature protein CD81 was fused with BAY 55-9837 to obtain MBAY with sustained-release capability.
MBAY was fabricated via genetic engineering, and the dissociation constant (Kd) was determined to assess its affinity for vasoactive intestinal peptide receptor type 2 (VPACII). Subsequently, MABY was incorporated into exosomes through electroporation to obtain MBAY-exosome, and SPOIN was adorned on MBAY-exosome by means of the self-assembly of transferrin (Tf) and the transferrin receptor (TfR). The in vitro release profile and in vivo pharmacokinetic profile of MBAY-Exosome-SPION were detected using high-performance liquid chromatography (HPLC). The L9(3) orthogonal design approach was utilized to optimize the drug administration mode in vivo. The therapeutic effect of MBAY-exosome-SPIONs/MF on T2DM was assessed both in vitro and in vivo.
In vitro studies showed that the release rate of MBAY from exosome-SPION was slower compared with BAY 55-9837. Meanwhile, MBAY still maintained high affinity and selectivity for VPAC II and MBAY-exosome-SPIONs/MF could effectively promote insulin secretion in response to elevated GLC as BAY-exosome-SPIONs/MF. In vivo studies indicated that MBAY-exosome-SPIONs had a prolonged half-life and improved pharmacokinetic parameters compared to BAY-exosome-SPIONs, which further alleviated the symptoms of T2DM model mice.
Thus, the reconstructed MBAY loaded in SPION-exosome realized sustained-release and exosomes-SPIONS achieved pancreatic targeting which led to ideal therapeutic effect in T2DM mice.
BAY55-9837是一种用于治疗2型糖尿病（T2DM）的潜在治疗性肽，可诱导葡萄糖（GLC）依赖性胰岛素分泌。我们之前的研究表明，使用超顺磁性氧化铁纳米颗粒修饰的外泌体（exosome-SPION）和外部磁力（MF）可使BAY 55-9837靶向胰岛。然而，exosome-SPION中负载的BAY 55-9837的初始突释缩短了其体内半衰期，从而降低了GLC反应性的频率。因此，在我们的研究中，将外泌体标志性蛋白CD81的跨膜疏水结构与BAY 55-9837融合，以获得具有缓释能力的MBAY。
通过基因工程制备MBAY，并测定其解离常数（Kd）以评估其对2型血管活性肠肽受体（VPACII）的亲和力。随后，通过电穿孔将MABY掺入外泌体中以获得MBAY-外泌体，并通过转铁蛋白（Tf）和转铁蛋白受体（TfR）的自组装将SPOIN装饰在MBAY-外泌体上。使用高效液相色谱（HPLC）检测MBAY-Exosome-SPION的体外释放曲线和体内药代动力学曲线。采用L9(3)正交设计方法优化体内给药方式。在体外和体内评估MBAY-外泌体-SPIONs/MF对T2DM的治疗效果。
体外研究表明，与BAY 55-9837相比，MBAY从exosome-SPION中的释放速率较慢。同时，MBAY对VPAC II仍保持高亲和力和选择性，并且MBAY-外泌体-SPIONs/MF可像BAY-外泌体-SPIONs/MF一样有效地促进胰岛素分泌以响应升高的GLC。体内研究表明，与BAY-外泌体-SPIONs相比，MBAY-外泌体-SPIONs具有更长的半衰期和改善的药代动力学参数，这进一步减轻了T2DM模型小鼠的症状。
因此，负载在SPION-外泌体中的重组MBAY实现了缓释，并且外泌体-SPIONS实现了胰腺靶向，从而在T2DM小鼠中产生了理想的治疗效果。
