Taming the Tumor Stroma: A Two-Stage Targeted Nanocapsule for Potent Deep Chemo-Immunotherapy in Triple-Negative Breast Cancer

TL;DR

A new two-stage nanocapsule targets both tumor cells and cancer-associated fibroblasts in triple-negative breast cancer, improving drug delivery and immune response.

Contribution

A TME-responsive nanocapsule that sequentially targets CAFs and cancer cells in TNBC is developed.

Findings

NPC-ABS/FDS showed 2.5-fold and 4.3-fold increased uptake of baicalein and doxorubicin, respectively.

The nanocapsule reduced CAF activation and improved immune cell infiltration in tumors.

It demonstrated prolonged tumor retention and enhanced drug penetration in TNBC.

Abstract

Background: The tumor microenvironment (TME) poses significant challenges to effective therapy, with cancer-associated fibroblasts (CAFs) playing a key role in tumor progression and drug resistance in triple-negative breast cancer (TNBC). Herein, a TME responsive nanocapsule, NPC-ABS/FDS, was developed utilizing baicalein, a CAFs modulator, and the cytotoxic drug doxorubicin to selectively target CAFs and tumor cells, respectively, in a stepwise manner. Methods: NPC-ABS/FDS was designed with CD13-mediated primary targeting for tumor accumulation and secondary targeting via σ-receptor binding (ABS nanoparticles) for CAFs and folate modification (FDS nanoparticles) for cancer cells. Physicochemical properties were assessed using TEM, particle size, and ζ-potential analyses. Fluorescence imaging evaluated tumor retention, while cellular uptake and TME modulation were analyzed in vitro and in vivo. Results: The successful preparation of NPC-ABS/FDS was demonstrated by its uniform morphology, stable characteristics, charge reversal, and increased particle size. Fluorescence imaging confirmed prolonged peritumoral retention. Cellular uptake increased 2.5-fold for baicalein in CAFs and 4.3-fold for doxorubicin in cancer cells. NPC-ABS/FDS downregulated α-SMA and FAP, reducing CAFs activation, improving intratumoral drug penetration, and enhancing CD8+ and CD4+ T cell infiltration while decreasing regulatory T cells. Conclusions: NPC-ABS/FDS effectively modulates multiple TME components, including CAFs and immune cells, and improves drug delivery in TNBC. These findings may support the development of improved therapeutic approaches for TNBC.

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