Cheng Liting, Ma Zhongyi, Yang Xinlin, Wang Xue, Wang Yuqiong, Liu Xinlong, Tang Zhongjie, Jang Dingxi, Liao Guojian, Liu Tongbao, Wu Shuang, Li Chong
Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Asian J Pharm Sci. 2025 Aug;20(4):101053. doi: 10.1016/j.ajps.2025.101053. Epub 2025 Mar 30.
Cryptococcosis, a serious systemic fungal infection caused by () and its variants, poses a significant clinical challenge due to its poor prognosis and severe health implications. The treatment of cryptococcal infections is complicated by several unique factors, stemming from both the pathogenic characteristics of the fungi and the biological barriers they exploit. These include the fungi's protective capsule, their ability to reside within host macrophages-thereby evading pharmacological intervention-and their involvement in multi-organ infections such as the lung and brain, in particular their strategic positioning within the brain, protected by the blood-brain barrier (BBB). To overcome these obstacles, precise active targeting emerges as a pivotal strategy. Identifying common targets is imperative to enhance therapeutic efficacy while ensuring the druggability of delivery systems. However, research on the methodology for selecting such shared targets remains sparse. In our investigation, we have pioneered the use of secreted proteins as shared target to trace the pathogens and their infection pathways. We identified the mannoprotein Cig1, prominently expressed on the surfaces of infected macrophages, lungs, and brains, as a viable shared target. On this basis, we utilized Hemin, a ligand for Cig1, to design liposomes (Hemin Lip) tailored for addressing complex fungal infections. By leveraging the interaction with the secreted protein Cig1, Hemin Lip specifically identifies and binds to organs and macrophages harboring cryptococcal infections, thereby facilitating targeted and efficacious clearance of both intracellular and extracellular fungus. Moreover, we have extended this targeting mechanism to other nanomedicinal platforms, including albumin nanoparticles. This study proposes an innovative drug delivery model that targets extracellular secretory proteins within the infection microenvironment, offering a streamlined formulation with the potential for effective therapy against complex infections.
隐球菌病是由新型隐球菌及其变种引起的一种严重的系统性真菌感染，因其预后不良和严重的健康影响而构成重大的临床挑战。隐球菌感染的治疗因几个独特因素而变得复杂，这些因素既源于真菌的致病特性，也源于它们利用的生物屏障。这些因素包括真菌的保护性荚膜、它们驻留在宿主巨噬细胞内的能力（从而逃避药物干预）以及它们参与多器官感染，如肺部和脑部感染，特别是它们在脑部的战略定位，受到血脑屏障（BBB）的保护。为了克服这些障碍，精确的主动靶向成为关键策略。确定共同靶点对于提高治疗效果同时确保递送系统的可药用性至关重要。然而，关于选择此类共同靶点的方法的研究仍然很少。在我们的研究中，我们率先使用分泌蛋白作为共同靶点来追踪病原体及其感染途径。我们确定了甘露糖蛋白Cig1，它在受感染的巨噬细胞、肺部和脑部表面显著表达，是一个可行的共同靶点。在此基础上，我们利用Cig1的配体血红素设计了用于解决复杂真菌感染的脂质体（血红素脂质体）。通过利用与分泌蛋白Cig1的相互作用，血红素脂质体特异性识别并结合含有隐球菌感染的器官和巨噬细胞，从而促进细胞内和细胞外真菌的靶向有效清除。此外，我们已经将这种靶向机制扩展到其他纳米药物平台，包括白蛋白纳米颗粒。本研究提出了一种针对感染微环境中细胞外分泌蛋白的创新药物递送模型，提供了一种简化的制剂，具有有效治疗复杂感染的潜力。
