Wu Lin, Liu Yang, Fu Ziqi, Guo Honglei, Liu Kang, Ren Jiafa, Huang Zhimin, Yang Fang, Mao Huijuan
Department of Nephrology, First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, 210029, P.R. China.
State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, 210096, P. R. China.
J Nanobiotechnology. 2025 May 30;23(1):398. doi: 10.1186/s12951-025-03487-8.
Glucocorticoid (GC) intolerance and systemic toxicity pose significant challenges in the treatment of primary nephrotic syndrome (PNS), underscoring the urgent need for targeted therapies that maximize efficacy while minimizing adverse effects. To address these challenges, we developed TRPC6-targeted dexamethasone-loaded nanobubbles (Dex@NBs-TRPC6)-an innovative therapeutic platform that enables selective podocyte delivery alongside real-time monitoring capabilities.
The Dex@NBs-TRPC6 nanobubble system comprises polyethylene glycol-modified lipid vesicles encapsulating dexamethasone (Dex), conjugated with TRPC6-specific antibody for precise podocyte targeting delivery. Comprehensive in vivo and in vitro evaluations demonstrated the robust kidney and podocyte-targeting capabilities of Dex@NBs-TRPC6. Functional assays in mouse podocyte cells revealed that Dex@NBs-TRPC6 significantly outperformed free Dex and non-targeted nanobubbles (Dex@NBs) in mitigating cell apoptosis and inflammation. In an adriamycin-induced mouse nephropathy model, Dex@NBs-TRPC6, administered at half the dosage of free Dex, markedly alleviated proteinuria, glomerular and tubular damage, renal apoptosis, inflammation and fibrosis. Notably, Dex@NBs-TRPC6 attenuated the overexpression of hepatic gluconeogenic genes PCK1 and GCP6, a common adverse effect associated with Dex. Furthermore, leveraging the acoustic response properties of Dex@NBs-TRPC6, this delivery system integrates ultrasound imaging capabilities, enabling real-time visualization and therapeutic monitoring.
By simultaneously enhancing therapeutic efficacy, minimizing systemic toxicity, and enabling personalized imaging-guided treatment, Dex@NBs-TRPC6 introduces a transformative approach to GC-based renal therapy.
糖皮质激素（GC）不耐受和全身毒性在原发性肾病综合征（PNS）的治疗中构成了重大挑战，这突出表明迫切需要开发靶向疗法，以在将不良反应降至最低的同时最大化疗效。为应对这些挑战，我们开发了靶向瞬时受体电位阳离子通道蛋白6（TRPC6）的载地塞米松纳米气泡（Dex@NBs-TRPC6）——一种创新的治疗平台，可实现足细胞的选择性递送并具备实时监测能力。
Dex@NBs-TRPC6纳米气泡系统由包裹着地塞米松（Dex）的聚乙二醇修饰脂质体组成，并与TRPC6特异性抗体偶联，用于精确的足细胞靶向递送。全面的体内和体外评估证明了Dex@NBs-TRPC6强大的肾脏和足细胞靶向能力。对小鼠足细胞进行的功能测定表明，在减轻细胞凋亡和炎症方面，Dex@NBs-TRPC6显著优于游离地塞米松和非靶向纳米气泡（Dex@NBs）。在阿霉素诱导的小鼠肾病模型中，以游离地塞米松一半的剂量给药，Dex@NBs-TRPC6显著减轻了蛋白尿、肾小球和肾小管损伤、肾脏细胞凋亡、炎症和纤维化。值得注意的是，Dex@NBs-TRPC6减弱了肝脏糖异生基因磷酸烯醇式丙酮酸羧激酶1（PCK1）和葡萄糖-6-磷酸酶催化亚基（GCP6）的过表达，这是与地塞米松相关的一种常见不良反应。此外，利用Dex@NBs-TRPC6的声学响应特性，该递送系统集成了超声成像能力，能够进行实时可视化和治疗监测。
通过同时提高治疗效果、最小化全身毒性并实现个性化成像引导治疗，Dex@NBs-TRPC6为基于糖皮质激素的肾脏治疗引入了一种变革性方法。
