Wu Can, Zhang Xiao Wei, Wang Manman, Sun Jinpan, Chen Jianfei, Guan Yanbin, Pang Xin
School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450046, China.
J Nanobiotechnology. 2025 Jan 31;23(1):66. doi: 10.1186/s12951-025-03143-1.
Chemotherapy remains an effective treatment for colon cancer but is hampered by its limited response rate. Bioactive peptides, marked with intracellular transformations, have been reported as an effective approach to boosting chemotherapeutic activity. Herein, a promising trypsin-responsive bioactive peptide-based nanodrug is constructed, which could significantly prolong the drug retention time in vivo by cascading transformations and improve chemotherapeutic efficacy. Initially, 1-Pept co-assembles with Dox into a few nanofibers called 1-Pept/Dox NFs, inducing an enhanced cellular uptake via caveolae-mediated endocytosis by avoiding lysosomal degradation and further promoting perinuclear transportation, thus enlarging the drug efficacy in target areas. After nanofiber disassembly, the released 1-Pept converts into Pept under the catalysis of intracellular overexpressed trypsin, which then reassembles into denser Pept NFs, inducing a cascade of effects including disruption of the cytoskeleton, mitochondrial dysfunction, and activation of caspase-3. By the synergism of Pept NFs and Dox, caspase-3 can be further activated, and cause greater damage to nuclear, thereby leading to tumor ablation. As the first example of employing trypsin-mediated nanodrugs with cascading transformations to promote chemotherapeutic activity, this work promises a strategy for novel therapies for efficiently combating colon cancer.
化疗仍然是结肠癌的一种有效治疗方法，但因其有限的反应率而受到阻碍。具有细胞内转化特征的生物活性肽已被报道为提高化疗活性的有效方法。在此，构建了一种有前景的基于胰蛋白酶响应性生物活性肽的纳米药物，它可以通过级联转化显著延长药物在体内的保留时间并提高化疗效果。最初，1-Pept与阿霉素共组装成一些称为1-Pept/阿霉素纳米纤维（1-Pept/Dox NFs）的纳米纤维，通过避免溶酶体降解并进一步促进核周运输，经小窝介导的内吞作用诱导增强的细胞摄取，从而扩大药物在靶区域的疗效。纳米纤维解体后，释放的1-Pept在细胞内过表达的胰蛋白酶催化下转化为Pept，然后重新组装成更致密的Pept纳米纤维，引发一系列效应，包括细胞骨架破坏、线粒体功能障碍和半胱天冬酶-3激活。通过Pept纳米纤维和阿霉素的协同作用，半胱天冬酶-3可被进一步激活，并对细胞核造成更大损伤，从而导致肿瘤消融。作为利用具有级联转化的胰蛋白酶介导纳米药物来促进化疗活性的首个实例，这项工作有望为有效对抗结肠癌的新疗法提供一种策略。
