Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China; College of Stomatology, Shanghai Jiao Tong University & National Center for Stomatology, Shanghai 200011, PR China; National Clinical Research Center for Oral Diseases & Shanghai Key Laboratory of Stomatology, Shanghai 200011, PR China.
Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China; College of Stomatology, Shanghai Jiao Tong University & National Center for Stomatology, Shanghai 200011, PR China; National Clinical Research Center for Oral Diseases & Shanghai Key Laboratory of Stomatology, Shanghai 200011, PR China.
Colloids Surf B Biointerfaces. 2024 Apr;236:113713. doi: 10.1016/j.colsurfb.2023.113713. Epub 2023 Dec 19.
Adjuvant therapy following surgery is imperative for enhancing the prognosis of patients with oral squamous cell carcinoma (OSCC) in the clinical setting. Nevertheless, challenges such as treatment resistance mediated by the tumor microenvironment (TME), systemic toxicity, and adverse side effects hinder the effectiveness of conventional adjuvant therapy. In this context, we introduce a novel nanocatalyst denoted as MnO@HA-CCM (MnHA@CCM NC) designed specifically for treating OSCC. This nanocatalyst exerts targeted anti-tumor effects through TME-activatable chemodynamic therapy (CDT) and tumoricidal autophagy. The MnHA@CCM NCs exploit the biocompatibility of hyaluronic acid (HA) coating and the homologous targeting effect of cancer cell membrane (CCM) camouflage, ensuring safe in vivo delivery and specific accumulation at tumor sites. Following intracellular uptake, Fenton-like Mn is generated by consuming glutathione (GSH) within the TME. Subsequently, Mn catalyzes the overproduced HO to generate reactive oxygen species (ROS), inducing cell apoptosis through mitochondrial damage. Additionally, phagocytized NCs and the resultant ROS accumulation in tumor cells elevate the autophagy flux, leading to autophagosome overload and consequent tumoricidal autophagy. Notably, normal cells without TME-catalytic CDT undergo mild protective autophagy to rebalance the stimulation of NCs. As a result, the TME-activatable MnHA@CCM NCs demonstrate a therapeutic efficacy in inhibiting cancer cell growth both in vitro and in vivo. This study presents a targeted treatment strategy for OSCC tumors while sparing normal cells, offering a potential alternative in the realm of adjuvant therapy.
术后辅助治疗对于提高口腔鳞状细胞癌（OSCC）患者的临床预后至关重要。然而，肿瘤微环境（TME）介导的治疗抵抗、全身毒性和不良反应等挑战，限制了传统辅助治疗的效果。在这种情况下，我们引入了一种新型纳米催化剂，命名为 MnO@HA-CCM（MnHA@CCM NC），专门用于治疗 OSCC。该纳米催化剂通过 TME 激活的化学动力学治疗（CDT）和杀肿瘤自噬发挥靶向抗肿瘤作用。MnHA@CCM NC 利用透明质酸（HA）涂层的生物相容性和癌细胞膜（CCM）伪装的同源靶向效应，确保在体内安全递送并在肿瘤部位特异性积累。细胞内摄取后，Fenton 样 Mn 通过消耗 TME 中的谷胱甘肽（GSH）生成。随后，Mn 催化过表达的 HO 生成活性氧（ROS），通过线粒体损伤诱导细胞凋亡。此外，被吞噬的 NC 和肿瘤细胞中产生的 ROS 积累会增加自噬通量，导致自噬体过载和随后的杀肿瘤自噬。值得注意的是，没有 TME 催化 CDT 的正常细胞会经历轻度保护性自噬，以重新平衡 NC 的刺激。因此，TME 激活的 MnHA@CCM NC 在体外和体内均显示出抑制癌细胞生长的治疗效果。这项研究为 OSCC 肿瘤提供了一种靶向治疗策略，同时保护正常细胞，为辅助治疗领域提供了一种潜在的替代方案。
