Cancer stem cells (CSCs), which are resistant to the traditional therapies, have been considered to account for the development, metastasis, and relapse of various malignant tumors, and therefore, must be eliminated to cure cancer. However, they can reside in deep tumor regions away from the blood vessels, and are typically inaccessible owing to the low delivery efficiency and limited tumor penetrating ability of drug carriers. To overcome these problems, we designed a tumor-penetrating peptide (tLyP-1)-conjugated ZIF-90 nanosystem loaded with doxorubicin (DOX) and N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT) to penetrate and eradicate differentiated cancer cells and CSCs simultaneously. The nanosystem exhibited beneficial biocompatibility, enhanced tissue penetration, high blood circulation stability, and pH-responsive drug release for favoring cancer therapy. It was found that the nanosystem could kill both cancer cells and CSCs in vitro. The in vivo results demonstrated that the ZIF-90 nanosystem can effectively accumulate in tumor tissues after long blood circulation and flexibly permeate throughout the tumor tissues. In the HCCLM3 xenograft model, the ZIF-90 nanosystem presented high-efficiency tumor suppression and drastically eradicated the CSCs in the tumor tissues with low systemic toxicity. Overall, the deep tumor-penetrating nanosystem exhibits outstanding potential for improving curative effect.

对传统疗法具有抗性的癌症干细胞（CSC）被认为是各种恶性肿瘤发生，转移和复发的原因，因此必须消除以治疗癌症。然而，它们可以驻留在远离血管的较深的肿瘤区域中，并且由于药物载体的低递送效率和有限的肿瘤穿透能力而通常不可接近。为克服这些问题，我们设计了负载阿霉素（DOX）和N- [N-（3,5-二氟苯乙酰基）-1-丙氨酰] -S-的肿瘤穿透肽（tLyP-1）-缀合的ZIF-90纳米系统。苯基甘氨酸叔丁酯（DAPT）可以同时穿透并根除分化的癌细胞和CSC。纳米系统表现出有益的生物相容性，增强的组织渗透性，较高的血液循环稳定性，pH响应药物释放有利于癌症治疗。发现纳米系统可以杀死癌细胞和CSC体外。该体内结果表明，ZIF-90纳米系统能有效地积累在肿瘤组织长的血液循环后且灵活地渗透在整个肿瘤组织。在HCCLM3异种移植模型中，ZIF-90纳米系统表现出高效的肿瘤抑制作用，并以低全身毒性彻底清除了肿瘤组织中的CSC。总体而言，深层穿透肿瘤的纳米系统具有提高疗效的显着潜力。