Oral Doxorubicin Lipid Nanoparticles Enhance Triple‐Negative Breast Cancer Therapy via Immune Activation and Reduced Cardiotoxicity

Abstract Doxorubicin (Dox) is a cornerstone chemotherapeutic agent for treating triple‐negative breast cancer, but its clinical utility is limited by cardiotoxicity. While oral administration can circumvent the toxicity risks of intravenous delivery by enabling gradual pharmacokinetics (PK), controlled systemic exposure, and reduced toxicity peaks, Dox faces critical barriers to gastrointestinal (GI) absorption, including poor intestinal permeability, extensive hepatic first‐pass metabolism, and inherent GI toxicity. To address these challenges, an orally deliverable lipid nanoparticle (Dox‐LP) encapsulating a Dox‐sodium taurodeoxycholate complex, engineered to enhance bioavailability while mitigating cardiotoxicity and GI damage, is developed. This study demonstrates that Dox‐LP leverages dual absorption pathways, lymphatic and venous, to achieve prolonged systemic retention and enhanced tumor accumulation. This optimized PK profile significantly reduces systemic toxicity compared to intravenous Dox. Notably, Dox‐LP exerts potent antitumor efficacy via a dual mechanism: direct induction of DNA damage and immunogenic cell death (ICD). ICD activation triggers robust antitumor immunity, characterized by dendritic cell maturation, expansion of cytotoxic CD8 + T cells, and suppression of immunosuppressive regulatory T cells (T reg cells) and myeloid‐derived suppressor cells. Collectively, the Dox‐LP platform represents a novel therapeutic strategy for TNBC, synergizing enhanced efficacy with reduced toxicity through tailored oral delivery and immune modulation.