Dual-Targeting iRGD-Functionalized Pentablock Copolymer Nanosystem for miR-345-5p and Gemcitabine Delivery to Pancreatic Tumors

Sep 22, 2026

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Effective therapies for pancreatic ductal adenocarcinoma (PDAC) have remained limited. Conventional chemotherapies for pancreatic cancer face dose-limiting toxicities, drug resistance, poor biodistribution, and extensive desmoplasia. To overcome these barriers, a tumor-guided dual-targeting nanosystem was developed for codelivery of miR-345 and gemcitabine. The construct uses pentablock copolymer chemistry for selective endolysosomal escape and iRGD (mGP-i) for passive and active tumor targeting.

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Abstract

Introduction

This article is licensed under CC-BY-NC-ND 4.0 [www.acsami.org](www.acsami.org) Research Article Dual-Targeting iRGD-Functionalized Pentablock Copolymer Nanosystem for miR-345-5p and Gemcitabine Delivery to Pancreatic Tumors Brianna M. White, Sirpu Natesh Nagabhishek, Susheel Kumar Nethi, Khloe Dao, Blake M. Arciga, Chandrashekara Puthanpura Mahadevappa, Jack Girton, Ratul Chowdhury, Satyanarayana Rachagani, * and Surya K. Mallapragada * Cite This: ACS Appl. Mater. Interfaces 2026, 18, 29564−29579 Read Online | | | | | | | | --- | --- | --- | --- | --- | --- | | ACCESS | Metrics & More | | Article Recommendations | | *sı Supporting Information | ABSTRACT: Effective therapies for pancreatic ductal adenocarcinoma (PDAC) have remained limited. Conventional chemotherapies for pancreatic cancer (PC) suffer from dose-limiting toxicities and limited efficacy due to drug resistance, poor biodistribution, and extensive desmoplasia. Targeted delivery of microRNAs to modify the tumor microenvironment, in combination with chemotherapeutics, can enhance outcomes by mitigating off-target toxicity and reducing fibrosis and drug resistance associated with PC therapies. To address these challenges, we developed a tumor-guided dual-targeting nanosystem for the codelivery of miR-345 and gemcitabine. This system leverages the intrinsic chemistry of pentablock copolymers for selective endolysosomal escape in tumor cells as well as targeting through functionalization with the tumor-penetrating peptide iRGD (a multifunctional construct referred to as mGP-i). ThemGP-i nanosystem exploits both passive and active targeting mechanisms within the tumor microenvironment to enhance the selective uptake and synergistic activity of miR-345 and gemcitabine in pancreatic tumors. The mGP-i nanosystem exhibited stability against RNase degradation and serum proteins for 24 h, with rapid release of gemcitabine over 48 h and prolonged miR-345 release over 1 week. In vivo biodistribution studies following intravenous administration in mice bearing subcutaneous PC tumors showed rapid and selective accumulation of mGP-i within tumor tissues. In an orthotopic syngeneic pancreatic tumor mouse model, mGP-i treatment significantly reduced tumor burden and metastasis compared with the control. Immunohistochemical analysis of mGP-itreated tumors revealed reduced fibrosis and lower expression of the proliferation marker Ki-67, alongside increased TUNELpositive cells, indicating apoptosis. Moreover, E-cadherin expression increased, while vimentin expression decreased, suggesting a transition toward a less invasive phenotype with reduced metastatic potential. These findings highlight mGP-i as a promising platform for tumor-targeted combination therapies in pancreatic cancer. KEYWORDS: nanomaterial, therapeutic, engineering, miRNA, drug delivery 1. INTRODUCTION Current chemotherapy treatments for pancreatic ductaladenocarcinoma (PDAC) are largely ineffective, leading to the dismal 5-year overall survival rate of 13% in pancreatic cancer (PC) patients.1 Late-stage detection of PC, as well as poor biodistribution, dose-limiting toxicity, and drug resistance of traditional chemotherapies, are contributing factors to this poor prognosis.2 After surgical resection, gemcitabine (Gem) isone of the most commonly used first-line treatments for PC patients.3 However, PC often exhibits resistance to Gem, and higher dosages result in significant toxic side effects, with only minimal improvements in patient survival.4,5 Pancreatic cells that are resistant to Gem have been shown to up-regulate sonic hedgehog (SHH),6 which is a key regulator of epithelial-tomesenchymal transition (EMT), which further exacerbates the problem and can ultimately increase metastatic potential and drug resistance.7 Additionally, the extensive dense fibrotic tissue known as desmoplasia, which surrounds PC tumor cells, is also driven by SHH signaling.8,9 Desmoplasia creates a phy

FAQs

Why are conventional chemotherapies ineffective for PDAC?

They are limited by dose-limiting toxicities, poor biodistribution, drug resistance, and the dense desmoplasia that hinders drug penetration.

What is the design strategy of the dual-targeting nanosystem?

It codelivers miR-345 and gemcitabine using pentablock copolymers for endolysosomal escape and the iRGD peptide to enhance tumor-directed uptake.

What therapeutic effects were observed in tumor models?

In vivo studies showed selective tumor accumulation, reduced tumor burden and metastasis versus controls, decreased fibrosis and Ki-67, increased TUNEL-positive apoptosis cells, and an EMT shift with higher E-cadherin and lower vimentin.

Sep 22, 2026

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