Xia Fangfang, Duan Qiao, Zhang Qing, Feng Wenqi, Ding Ding, Ji Ding-Kun, Wang Xiang, Tan Weihong
Shanghai Institute of virology, Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China.
Shanghai Institute of virology, Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, PR China.
Acta Biomater. 2025 Mar 1;194:364-372. doi: 10.1016/j.actbio.2025.01.037. Epub 2025 Jan 23.
Aptamers and aptamer-drug conjugates (ApDCs) have shown some success as targeted therapies in cancer theranostics. However, their stability in complex media and their capacity to evade lysosomal breakdown still need improvement. To address these challenges, we herein developed a one-step self-assembly strategy to improve the stability of aptamers or ApDCs, while simultaneously enhancing their delivery performance and therapeutic efficiency through a lysosome-independent pathway. This strategy involves the formation of stable complexes between disulfide monomer and aptamers (Sgc8) or ApDCs (Gem-Sgc8). Self-assembled Sgc8 NPs resisted nuclease degradation for up to 24 h, whereas the aptamer alone degraded within just 3 h. These self-assembled Sgc8 NPs, as well as Gem-Sgc8 NPs, demonstrated enhanced binding capabilities compared to Sgc8 aptamers or Gem-Sgc8 alone. Furthermore, lysosome-independent cellular uptake was significantly improved, which in turn increased the therapeutic efficacy of Gem-Sgc8 NPs by 2.5 times compared to Gem-Sgc8 alone. In vivo results demonstrated that Gem-Sgc8 NPs can effectively suppress the growth of tumors. The same self-assembly strategy was successfully applied to other aptamers, such as MJ5C and cMET, showing the generalizability of our method, Overall, this aptamer self-assembly strategy not only overcomes the limitations associated with instability and lysosomal degradation but also demonstrates its broad applicability, highlighting its potential as a promising avenue for advancing targeted cancer theranostics. STATEMENT OF SIGNIFICANCE: We developed a one-step self-assembly strategy to improve the stability of aptamers or ApDCs and enhance their drug therapeutic efficiency through a lysosome-independent pathway. The stability of self-assembled Sgc8 nanoparticles (NPs) was significantly improved. The resulting Sgc8 NPs or GEM-Sgc8 NPs exhibited enhanced binding ability compared to Sgc8 aptamers or GEM-Sgc8 alone, and they also facilitated lysosome-independent cellular uptake, resulting in a 2.5-fold increase in therapeutic efficacy of GEM-Sgc8-NPs. The same self-assembly strategy was successfully applied to other aptamers, such as MJ5C and cMET, showing the generalizability of our method.
适体和适体-药物偶联物（ApDCs）在癌症诊疗的靶向治疗中已取得了一些成效。然而，它们在复杂介质中的稳定性以及逃避溶酶体降解的能力仍有待提高。为应对这些挑战，我们在此开发了一种一步自组装策略，以提高适体或ApDCs的稳定性，同时通过不依赖溶酶体的途径增强其递送性能和治疗效率。该策略涉及二硫键单体与适体（Sgc8）或ApDCs（Gem-Sgc8）之间形成稳定的复合物。自组装的Sgc8纳米颗粒（NPs）在长达24小时内抵抗核酸酶降解，而单独的适体在仅3小时内就会降解。这些自组装的Sgc8 NPs以及Gem-Sgc8 NPs与单独的Sgc8适体或Gem-Sgc8相比，表现出增强的结合能力。此外，不依赖溶酶体的细胞摄取显著改善，这反过来使Gem-Sgc8 NPs的治疗效果比单独的Gem-Sgc8提高了2.5倍。体内结果表明，Gem-Sgc8 NPs能有效抑制肿瘤生长。相同的自组装策略成功应用于其他适体，如MJ5C和cMET，表明我们方法的通用性。总体而言，这种适体自组装策略不仅克服了与不稳定性和溶酶体降解相关的局限性，还展示了其广泛的适用性，突出了其作为推进靶向癌症诊疗的有前景途径的潜力。重要意义声明：我们开发了一种一步自组装策略，以提高适体或ApDCs的稳定性，并通过不依赖溶酶体的途径提高其药物治疗效率。自组装的Sgc8纳米颗粒（NPs）的稳定性显著提高。与单独的Sgc8适体或Gem-Sgc8相比，所得的Sgc8 NPs或GEM-Sgc8 NPs表现出增强的结合能力，并且它们还促进了不依赖溶酶体的细胞摄取，导致GEM-Sgc8-NPs的治疗效果提高了2.5倍。相同的自组装策略成功应用于其他适体，如MJ5C和cMET，表明我们方法的通用性。
