microRNAs(miRs)的失调是三阴性乳腺癌(TNBC)的标志,与它的成长密切相关,转移,和复发。失调的miR是TNBC治疗的有希望的目标,然而,肿瘤中多种无序miRs的靶向和准确调控仍是一个巨大的挑战。这里,据报道,一种多靶向和按需的非编码RNA调控纳米平台(MTOR)可以精确调控无序的miR,导致TNBC生长的戏剧性抑制,转移,和复发。在长期血液循环的帮助下,位于多功能外壳中的尿激酶型纤溶酶原激活物肽和透明质酸的配体使MTOR能够主动靶向TNBC细胞和乳腺癌干细胞样细胞(BrCSC)。进入TNBC细胞和BrCSCs后,MTOR经历溶酶体透明质酸酶诱导的壳脱离,导致富含TAT的核心爆炸,从而增强核目标。随后,MTOR可以精确地同时下调TNBC中microRNA-21的表达和上调microRNA-205的表达。在皮下异种移植物中,原位异种移植物,肺转移,和复发TNBC小鼠模型,MTOR在抑制肿瘤生长方面表现出显著的协同作用,转移,并且由于其对无序miRs的按需调节而复发。这种MTOR系统为按需调控无序miRs对抗增长开辟了一条新途径,转移,TNBC复发。
Dysregulation of microRNAs (miRs) is the hallmark of triple-negative breast cancer (TNBC), which is closely involved with its growth, metastasis, and recurrence. Dysregulated miRs are promising targets for TNBC therapy, however, targeted and accurate regulation of multiple disordered miRs in tumors is still a great challenge. Here, a multi-targeting and on-demand non-coding RNA regulation nanoplatform (MTOR) is reported to precisely regulate disordered miRs, leading to dramatical suppression of TNBC growth, metastasis, and recurrence. With the assistance of long blood circulation, ligands of urokinase-type plasminogen activator peptide and hyaluronan located in multi-functional shells enable MTOR to actively target TNBC cells and breast cancer stem cell-like cells (BrCSCs). After entering TNBC cells and BrCSCs, MTOR is subjected to lysosomal hyaluronidase-induced shell detachment, leading to an explosion of the TAT-enriched core, thereby enhancing nuclear targeting. Subsequently, MTOR could precisely and simultaneously downregulate microRNA-21 expression and upregulate microRNA-205 expression in TNBC. In subcutaneous xenograft, orthotopic xenograft, pulmonary metastasis, and recurrence TNBC mouse models, MTOR shows remarkably synergetic effects on the inhibition of tumor growth, metastasis, and recurrence due to its on-demand regulation of disordered miRs. This MTOR system opens a new avenue for on-demand regulation of disordered miRs against growth, metastasis, and recurrence of TNBC.