Multifunctional elastin-like polypeptide nanocarriers for efficient miRNA delivery in cancer therapy

3.0 科研～小助 2025-09-01 4 4 14.18MB 24 页 1知币

Hongetal. Journal of Nanobiotechnology (2024) 22:293

https://doi.org/10.1186/s12951-024-02559-5

RESEARCH Open Access

permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the

original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or

other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line

to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory

regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this

licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco

mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Journal of Nanobiotechnology

Multifunctional elastin-like polypeptide

nanocarriers forecient miRNA delivery

incancer therapy

Jisan Hong1, Dahye Sim1, Byung‑Heon Lee1, Vijaya Sarangthem1* and Rang‑Woon Park1*

Abstract

Background The exogenous delivery of miRNA to mimic and restore miRNA‑34a activity in various cancer models

holds signiﬁcant promise in cancer treatment. Nevertheless, its eﬀectiveness is often impeded by challenges, includ‑

ing a short half‑life, propensity for oﬀ‑target accumulation, susceptibility to inactivation by blood‑based enzymes,

concerns regarding patient safety, and the substantial cost associated with scaling up. As a means of overcoming

these barriers, we propose the development of miRNA‑loaded Tat‑A86 nanoparticles by virtue of Tat‑A86’s ability

to shield the loaded agent from external environmental factors, reducing degradation and inactivation, while enhanc‑

ing circulation time and targeted accumulation.

Results Genetically engineered Tat‑A86, featuring 16 copies of the interleukin‑4 receptor (IL‑4R)‑binding peptide

(AP1), Tat for tumor penetration, and an elastin‑like polypeptide (ELP) for presenting target ligands and ensuring

stability, served as the basis for this delivery system. Comparative groups, including Tat‑E60 and A86, were employed

to discern diﬀerences in binding and penetration. The designed ELP‑based nanoparticle Tat‑A86 eﬀectively con‑

densed miRNA, forming stable nanocomplexes under physiological conditions. The miRNA/Tat‑A86 formulation

bound speciﬁcally to tumor cells and facilitated stable miRNA delivery into them, eﬀectively inhibiting tumor growth.

The eﬃcacy of miRNA/Tat‑A86 was further evaluated using three‑dimensional spheroids of lewis lung carcinoma

(LLC) as in vitro model and LLC tumor‑bearing mice as an in vivo model. It was found that miRNA/Tat‑A86 facilitates

eﬀective cell killing by markedly improving miRNA penetration, leading to a substantial reduction in the size of LLC

spheroids. Compared to other controls, Tat‑A86 demonstrated superior eﬃcacy in suppressing the growth of 3D

cellular aggregates. Moreover, at equivalent doses, miRNA‑34a delivered by Tat‑A86 inhibited the growth of LLC cells

in allograft mice.

Conclusions Overall, these studies demonstrate that Tat‑A86 nanoparticles can deliver miRNA systemically, overcom‑

ing the basic hurdles impeding miRNA delivery by facilitating both miRNA uptake and stability, ultimately leading

to improved therapeutic eﬀects.

Keywords miRNA‑34a, Tumor targeting, ELP nanoparticle, IL‑4 receptor, Cell penetrating peptide, Apoptosis, 3D

spheroid, Tumor inhibition

*Correspondence:

Vijaya Sarangthem

devi1703@gmail.com

Rang‑Woon Park

nwpark@knu.ac.kr

Full list of author information is available at the end of the article

Page 2 of 24

Hongetal. Journal of Nanobiotechnology (2024) 22:293

Graphical Abstract

Introduction

MicroRNAs (miRNAs) have gained prominence in

cancer therapy because of their applications in can-

cer prognosis, pathogenesis, diagnosis, and treatment.

Comprising approximately 22 nucleotides in length,

miRNAs are small, highly conserved, and non-protein

coding molecules [1] that regulate gene expression,

inﬂuencing processes like cell growth, diﬀerentiation,

and death [2]. In cancer therapy, certain miRNAs can

function either as tumor suppressors or oncogenes, and

their targeted delivery to cancer cells can yield thera-

peutic beneﬁts [3]. e miR-34 family, along with the

let-7 and miR-200 families, collectively constitute the

three major tumor-suppressive miRNA families. Down-

regulation or loss of expression of miR-34a is linked to

various cancers, including glioblastomas and malig-

nant peripheral nerve sheath tumors, as well as breast,

colon, ovarian, pancreatic, and prostate cancers [4–10].

Evidence indicates that miR-34a directly targets the 3’

UTRs of diverse oncogenic mRNAs, including Bcl-2,

SIRT1, Fra-1, E2F, c-Met, Notch1, Notch2, CDK4/6,

VEGF, ARAF, PIK3R2, cyclin D3, cyclin E2, and PLK1

[6, 7, 10–15], which may explain its tumor-suppressing

properties. Moreover, low miR-34a expression corre-

lates with larger tumor size [16]. Recent breakthroughs

in the ﬁeld of miR-34a biology have sparked signiﬁcant

enthusiasm among biopharmaceutical companies.

MiRNA replacement therapy, which involves reintro-

ducing miRNAs into cancer cells to restore their normal

function, has been widely assessed in preclinical trials

[17, 18]. Particularly, microRNA-34a (or miR-34a) has

been extensively investigated as a potential candidate

for lung cancer therapy [19]. Restoring miRNA-34a lev-

els in pancreatic cancer promoted the downregulation

of Bcl-2 and Notch 1/2 expression, impeding cell growth

and invasion [20]. Furthermore, the decreased expres-

sion of miRNA-34a implicated both the development

and progression of epithelial ovarian cancer [5]. Notably,

enforced miRNA-34a expression inhibited cell growth

and promoted apoptosis in p53-mutant gastric cancer

cells [21]. However, despite evidence of the potential

anti-cancer eﬀects of miRNAs, their clinical application

is limited by practical challenges. e primary concern

when developing miRNA as new drugs is ensuring their

safety and eﬀectiveness. e key obstacles associated

with miRNA delivery include challenges in accessing the

target cells and the risk of oﬀ-target eﬀects. Moreover,

naked miRNA is ineﬀective due to its poor stability, short

half-life, and susceptibility to degradation or inactivation

by nucleic acid-degrading enzymes [22, 23]. erefore,

文档加载中……请稍候！
如果长时间未打开，您也可以点击刷新试试。

下载文档到电脑，查找使用更方便

1 知币 4人已下载

立即下载

Multifunctional elastin-like polypeptide nanocarriers for efficient miRNA delivery in cancer therapy.pdf

共24页,预览8页

还剩页未读，继续阅读

Multifunctional elastin-like polypeptide nanocarriers for efficient miRNA delivery in cancer therapy

相关推荐

开通VIP享超值会员特权

作者详情

相关内容

推荐作者

热门标签

举报选择: