@article{Zhang2026, 
author = {Yunyang Zhang and Siying Chen and Yuxin Wang and Jingjing Zhang and Xinyan Yang and Haoran Li and Hongxia Dai and Shibo Wang and M. Zubair Iqbal and Yao Li and Xiangdong Kong and Ruibo Zhao},
title = {Manganese mineralization based stromal depleter priming nanomedicine penetration for robust cancer therapy},
year = {2026},
journal = {Nano Research},
volume = {19},
number = {1},
pages = {94908058},
keywords = {manganese-based mimetic mineralization, TGF-β and associated proteins, tumor stromal, doxorubicin-loaded liposomes nanomedicines (Dox-LNP), drug penetration, triple-negative breast cancer therapy},
url = {https://www.sciopen.com/article/10.26599/NR.2025.94908058},
doi = {10.26599/NR.2025.94908058},
abstract = {Poor tumor penetration is a significant challenge for using nanoliposome-based chemotherapy for triple-negative breast cancer (TNBC). Recently, a milieu of biological cues downregulating tumor stroma has been associated with biological metal ions, primarily such as Mn2+. Inspired by this, we hypothesized that Mn2+ could serve as a functional component in designing an alternative modulator for the tumor stroma microenvironment by reducing its extracellular matrix, further decreasing its stromal density. Herein, we presented a novel extracellular matrix (ECM) depleter within a tumor involving manganese-based mineralization materials that primed inhibition of the extracellular matrix of cancer cells, demonstrating a facile strategy for improving drug penetration, delivery and therapy efficiency of the doxorubicin-loaded liposome nanoparticles (Dox-LNP). As a result, the manganese mimetic mineralization material, manganese phosphate (MnP), demonstrated controlled biodegradation and biocompatibility within tumor microenvironments. The release of Mn2+ from MnP within the cell lysosome or tumor microenvironment inhibited TGF-β expression and its downstream profibrotic signaling pathways, thereby reducing the tumor stroma density by suppressing the expression of α-smooth actin (α-SMA) and collagen I (COL-I), and inducing tumor stromal disruption both in vitro and in vivo. The typical nanomedicines, Dox-LNP, were subsequently used to check their penetration. The MnP pretreated tumor could significantly improve tumor penetration and accumulation of Dox-LNP, which demonstrated a significant improvement in the treatment of TNBC. These achievements proposed a successful tumor stromal regulation material involving manganese mineralization for priming tumor stromal depletion in situ by inhibiting the TGF-β and associated proteins, representing an alternative materials strategy to substitute biotechnology for stromal reduction, which may further represent a great potential of nanomedicine-based cancer therapy.}
}