Progress of siRNA Nanomedicines in Modulating the Microenvironment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and its poor prognosis, chemoresistance, and limited immunotherapy response are closely linked to pathological remodeling of the tumor microenvironment (TME). Targeting the TME has emerged as a promising strategy, but conventional agents such as monoclonal antibodies and small-molecule inhibitors are limited by undruggable targets, off-target toxicity, and poor tumor penetration. Small interfering RNA (siRNA) enables sequence-specific silencing of multiple TME-related genes-including TGF-β, PD-L1, and HIF-1α-offering a flexible approach to reverse immunosuppression, fibrosis, and hypoxia. However, poor in vivo stability and inefficient intratumoral delivery have hindered clinical translation. Recent advances in intelligent nanocarriers, including pH/enzyme-responsive and biomimetic membrane-coated systems, together with spatial omics-guided target selection, have substantially improved siRNA delivery and therapeutic efficacy. This review summarizes the immunoregulatory mechanisms and key targets within the TNBC microenvironment, the design principles and technological bottlenecks of siRNA nanodelivery systems, and emerging combination strategies with immune checkpoint inhibitors. It further discusses subtype-specific targeting needs, long-term resistance risks, and translational challenges from preclinical models to clinical applications, providing a systematic framework for siRNA nanomedicine-based remodeling of the TNBC microenvironment and highlighting critical directions for future precision combination therapy.