Manganese mineralization based stromal depleter priming nanomedicine penetration for robust cancer therapy

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.