Multi‐Targeted and On‐Demand Non‐Coding RNA Regulation Nanoplatform against Metastasis and Recurrence of Triple‐Negative Breast Cancer

Abstract

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.

Nanotechnology‐based CRISPR/Cas9 delivery system for genome editing in cancer treatment

“…PEI with low molecular weight has the advantage of low cytotoxicity, but to improve its transfection efficiency, many studies have introduced special groups or cross-linked them to enhance transfection. [140][141][142][143][144] Dahlman et al modified low molecular weight PEI (PEI600) with alkyl chains to realize effective siRNA deliver. 145 Guan et al synthesized fluorocarbon (FC) modified PEI600 for that purpose.…”

“…Compared to low molecular weight PEI, high molecular weight PEI often exhibits better transfection effectiveness, however, often has higher cytotoxicity. PEI with low molecular weight has the advantage of low cytotoxicity, but to improve its transfection efficiency, many studies have introduced special groups or cross‐linked them to enhance transfection 140–144 . Dahlman et al modified low molecular weight PEI (PEI600) with alkyl chains to realize effective siRNA deliver 145 .…”

Advances and applications of nanoparticles in cancer therapy

“…555 A large number of nuclear targeting NPs had been developed. 210,535,[556][557][558][559][560][561][562][563][564][565][566][567][568][569][570] For example, Ping et al 535 proposed a solution that could target the nucleus and expand the nuclear pores. On this basis, the solution was combined with a size reduction strategy, the in vitro and in vivo results showed that it could effectively enhance nuclear uptake and promote the delivery of nuclear-targeted anticancer drugs.…”

“…Therefore, it is necessary to construct a transport vector with nucleus targeting function to effectively deliver drugs 555 . A large number of nuclear targeting NPs had been developed 210,535,556–570 . For example, Ping et al 535 proposed a solution that could target the nucleus and expand the nuclear pores.…”

“…Recently, however, there has been an intense debate about the EPR effect, 207 which has been demonstrated in mouse tumor models, but not in clinical solid tumors. In that case, many endogenous components have been uncovered and applied to NPs for tumor targeting through observing the way cells interact in nature, which mainly include small molecules (folate [FA], 208 riboflavin 209 ), carbohydrates (galactose, glycans), targeting peptides (arginylglycylaspartic acid, 210 HIV trans‐activator of transcription 211 and Melittin 212 ), and so on.…”