Guo Juan, Pan Xueting, Wu Qingyuan, Li Ping, Wang Chaohui, Liu Shuang, Zhang Haoyuan, Huang Zezhong, Mou Xiaozhou, Liu Huiyu, Xue Jiajia
Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing University of Chemical Technology, Beijing, China.
Clinical Research Institute, Zhejiang provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang Province, China.
Signal Transduct Target Ther. 2025 Apr 25;10(1):137. doi: 10.1038/s41392-025-02217-8.
Addressing the critical biological barriers of targeted accumulation and deep tumor penetration remains essential for the clinical translation of nanomedicines. However, existing nanomedicines often face challenges during in vivo transportation, including immune clearance, tumor microenvironmental barriers, and limited vascular permeability, which collectively reduce drug delivery efficiency and compromise therapeutic efficacy. Here, we present a bio-barrier-adaptable biomimetic nanoplatform, MSF@CCM, which integrates a mesoporous silica-loaded iron oxyhydroxide (MSF) core camouflaged with a homologous membrane. This design conferred dual functionality: (1) enhanced tumor accumulation and immune evasion by exploiting homologous cell-cell interactions and mimicking "self" markers, thereby effectively bypassing macrophage clearance and surpassing the limitations of traditional targeted drug delivery; and (2) amplified ultrasound (US)-mediated intratumoral penetration. The MSF core, with its unique porous structure and rough surface, significantly enhanced US cavitation effects, transiently disrupting tumor vasculature and facilitating deep penetration of nanomedicines. Upon US triggering, MSF@CCM effectively disrupted intracellular redox homeostasis, potently inducing ferroptosis via lipid peroxidation accumulation, mitochondrial morphological changes, and decreased key protein expression. This combined therapeutic strategy achieved a remarkable 96.5% tumor growth inhibition in vivo while maintaining favorable biocompatibility. Our findings establish a novel paradigm for overcoming multidimensional bio-barriers through biohybrid engineering and physical energy synergy, offering a promising modality for enhanced cancer therapy.
解决靶向积累和肿瘤深部渗透的关键生物学障碍对于纳米药物的临床转化仍然至关重要。然而，现有的纳米药物在体内运输过程中往往面临挑战，包括免疫清除、肿瘤微环境屏障和有限的血管通透性，这些因素共同降低了药物递送效率并损害了治疗效果。在此，我们提出了一种生物屏障适应性仿生纳米平台，即MSF@CCM，它整合了负载有介孔二氧化硅的羟基氧化铁（MSF）核心，并由同源膜伪装。这种设计赋予了双重功能：（1）通过利用同源细胞间相互作用和模拟“自身”标记增强肿瘤积累和免疫逃逸，从而有效绕过巨噬细胞清除并超越传统靶向药物递送的局限性；（2）增强超声（US）介导的肿瘤内渗透。MSF核心具有独特的多孔结构和粗糙表面，显著增强了超声空化效应，短暂破坏肿瘤血管并促进纳米药物的深部渗透。在超声触发后，MSF@CCM有效破坏细胞内氧化还原稳态，通过脂质过氧化积累、线粒体形态变化和关键蛋白表达降低有力地诱导铁死亡。这种联合治疗策略在体内实现了高达96.5%的显著肿瘤生长抑制，同时保持了良好的生物相容性。我们的研究结果通过生物杂交工程和物理能量协同作用建立了一种克服多维生物屏障的新范式，为增强癌症治疗提供了一种有前景的模式。
