Liu Yi, Zhang Zheng, Du Huyang, Chen Xiangjun, Hu Nan, Yu Tingting, Hou Meili, Yu Xiaolin
College of Chemical Engineering, Sichuan University of Science & Engineering Zigong 643000 China
Institute of Precision Medicine, Zigong Academy of Big Data and Artificial Intelligence in Medical Science, Zigong Fourth People's Hospital Zigong 643000 China
RSC Adv. 2025 Jul 10;15(29):23966-23977. doi: 10.1039/d5ra03250d. eCollection 2025 Jul 4.
Chemoresistance poses a critical challenge in cancer therapy across diverse tumor types, including non-small cell lung cancer (NSCLC), where chemotherapy-induced neuroendocrine differentiation (NED) of tumor cells plays a pivotal role in acquiring treatment resistance. This process significantly reduces chemotherapy efficacy, accelerates tumor progression, and ultimately worsens patient survival outcomes. The complex mechanisms underlying chemoresistance involve multiple factors, including enhanced DNA repair pathways, increased drug efflux capacity, and alterations in gene expression. Additionally, the tumor microenvironment, a dynamic ecosystem surrounding cancer cells, fosters a protective niche that exacerbates chemotherapy resistance. To address this challenge, we propose an innovative nanocomposite hydrogel system for the co-delivery of cisplatin and short hairpin RNA (shRNA) targeting protein arginine methyltransferase 5 (PRMT5), a key gene implicated in drug resistance. This system utilizes polyethyleneimine-modified mesoporous silica nanoparticles, which serve as nanocarriers, encapsulating cisplatin within the mesopores and coating the surface with methacryloylated hyaluronic acid (HA-MA). The design enables tumor microenvironment-responsive drug release, triggered by hyaluronidase enzymes abundant within the tumor, resulting in nanoparticle disassembly and the release of cisplatin. Simultaneously, the delivery of shRNA silences PRMT5 expression, enhancing chemosensitivity. By integrating targeted gene therapy with chemotherapy, this system offers a promising strategy for overcoming chemoresistance in NSCLC. Targeting both cancer cells and their microenvironment, this approach holds potential to transform the treatment of chemotherapy-resistant cancers, advancing more effective and personalized oncological therapies.
化疗耐药性是各类肿瘤治疗中面临的一项严峻挑战，包括非小细胞肺癌（NSCLC），在该疾病中，化疗诱导的肿瘤细胞神经内分泌分化（NED）在获得治疗耐药性方面起着关键作用。这一过程显著降低了化疗疗效，加速了肿瘤进展，并最终恶化了患者的生存结果。化疗耐药性背后的复杂机制涉及多个因素，包括增强的DNA修复途径、增加的药物外排能力以及基因表达的改变。此外，肿瘤微环境是癌细胞周围的一个动态生态系统，它形成了一个保护性微环境，加剧了化疗耐药性。为应对这一挑战，我们提出了一种创新的纳米复合水凝胶系统，用于顺铂和靶向蛋白质精氨酸甲基转移酶5（PRMT5）的短发夹RNA（shRNA）的共递送，PRMT5是一个与耐药性相关的关键基因。该系统利用聚乙烯亚胺修饰的介孔二氧化硅纳米颗粒作为纳米载体，将顺铂封装在介孔内，并用甲基丙烯酰化透明质酸（HA-MA）包覆表面。这种设计能够实现肿瘤微环境响应性药物释放，由肿瘤内丰富的透明质酸酶触发，导致纳米颗粒解体并释放顺铂。同时，shRNA的递送使PRMT5表达沉默，增强了化疗敏感性。通过将靶向基因治疗与化疗相结合，该系统为克服NSCLC中的化疗耐药性提供了一种有前景的策略。针对癌细胞及其微环境，这种方法有望改变化疗耐药性癌症的治疗方式，推动更有效和个性化的肿瘤治疗。
