Tang Yan, Jia Changhao, Ning Honglong, Zhao Ying, Chang Qingcheng, Song Wenlin, Jin Taiwei, Zhang Xuenong
School of Pharmacy, Yancheng Teachers University, Yancheng 224002, China.
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
ACS Appl Mater Interfaces. 2025 Aug 13;17(32):45555-45568. doi: 10.1021/acsami.5c10486. Epub 2025 Jul 30.
The frequent occurrence of chemoresistance in breast tumors remains a challenge to achieving satisfactory therapeutic efficacy, and a smart drug delivery system with flexible properties is urgently needed to achieve an all-in-one combination anticancer therapy. In this study, an efficiency delivery system with a pH-triggered detachable PEG layer (sPEG) and a folic acid (FA)-modified cationic liposome core (FLip) is constructed for codelivering doxorubicin (DOX) and METTL3 siRNA (siMETTL3). The obtained codelivery nanoparticles (NPs), sPEG-FLip@DOX/siMETTL3, can maintain circulatory stability with minimized systemic toxicity, which is attributed to the negatively charged sPEG layer, and expose the positively charged FLip core in the weakly acidic extracellular environment to facilitate the internalization by MCF-7/ADR cells. Moreover, its targeting efficiency can be further enhanced by dexamethasone (Dex) pretreatment owing to the enhanced binding efficiency of FA to folate receptor α (FRα) and the reduced immune clearance of FA-functionalized NPs. After internalization via FA-FRα interactions, the positively charged FLip core induces the effective endosomal escape of codelivery NPs, accompanied by the release of DOX and siMETTL3. As a result, the levels of drug resistance-related proteins in tumors are significantly downregulated, and the enhanced chemotherapy and suppressed DOX resistance demonstrate superior tumor suppression in MCF-7/ADR tumor-bearing mice. This sequential therapy provides a reliable approach for improving cancer chemotherapy with suppressed DOX resistance by destroying the N6 methyladenosine (m6A) methylation, which may extremely benefit the future design of smart drug delivery systems.
乳腺癌中化疗耐药的频繁发生仍然是实现满意治疗效果的一个挑战，因此迫切需要一种具有灵活特性的智能药物递送系统来实现一体化联合抗癌治疗。在本研究中，构建了一种具有pH触发可分离聚乙二醇层（sPEG）和叶酸（FA）修饰阳离子脂质体核心（FLip）的高效递送系统，用于共递送阿霉素（DOX）和METTL3小干扰RNA（siMETTL3）。所获得的共递送纳米颗粒（NPs），即sPEG-FLip@DOX/siMETTL3，可通过带负电荷的sPEG层维持循环稳定性并将全身毒性降至最低，并在弱酸性细胞外环境中暴露带正电荷的FLip核心，以促进MCF-7/ADR细胞的内化。此外，由于FA与叶酸受体α（FRα）的结合效率提高以及FA功能化纳米颗粒的免疫清除减少，地塞米松（Dex）预处理可进一步提高其靶向效率。通过FA-FRα相互作用内化后，带正电荷的FLip核心诱导共递送纳米颗粒有效逃离内体，同时释放DOX和siMETTL3。结果，肿瘤中耐药相关蛋白的水平显著下调，增强的化疗和对DOX耐药的抑制在荷MCF-7/ADR肿瘤小鼠中表现出卓越的肿瘤抑制作用。这种序贯治疗通过破坏N6甲基腺苷（m6A）甲基化提供了一种可靠的方法来改善癌症化疗并抑制DOX耐药，这可能对未来智能药物递送系统的设计极为有益。
