Objectives: Talazoparib (TZL) is a potent PARP inhibitor but suffers from poor aqueous solubility, dissolution-limited absorption, and dose-limiting systemic toxicities, which together restrict its antitumor efficacy in some breast cancer settings. This study aimed to develop a stearic acid-based nanoemulsion (SANE) to improve the delivery of TZL and enhance its antitumor activity and preliminarily explore its impact on DNA damage response-related pathways. Methods: SANE-TZL was prepared using a high-pressure homogenization method, and its physicochemical properties were characterized. MCF-7 and MDA-MB-231 breast cancer cells were used to evaluate cellular uptake, cytotoxicity, and changes in key DNA damage response markers. In vivo therapeutic efficacy and safety were assessed in an MDA-MB-231 xenograft mouse model. Results: SANE-TZL exhibited a uniform particle size of approximately 118 nm with excellent stability. In MCF-7 cells, SANE-TZL significantly enhanced drug internalization, resulting in an 8.4-fold reduction in IC₅₀ compared to free TZL. Consistently, in MDA-MB-231 cells, SANE-TZL also showed markedly increased antiproliferative activity. At the molecular level, SANE-TZL modulated the expression of several DNA damage response-related genes, including BRCA1, RAD51, and SLFN11, in a manner consistent with impaired DNA repair capacity. In vivo, high-dose SANE-TZL achieved a tumor growth inhibition (TGI) rate of 58.55%, which was higher than that of the free TZL group (41.86%) and the blank eSANE group (17.59%). No evident hematological or organ toxicities were observed in the SANE-TZL-treated groups. Conclusions: SANE-TZL markedly improves the delivery efficiency and antitumor activity of TZL in breast cancer models while maintaining a favorable safety profile. By combining a functional stearic acid carrier with TZL, this nanoemulsion formulation represents a safe and potent strategy to enhance PARP inhibitor-based chemotherapy in breast cancer, and it may provide a basis for further mechanistic studies on DNA damage response modulation.

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality worldwide, primarily due to the systemic toxicity and drug resistance associated with conventional doxorubicin (DOX) therapy. To overcome these limitations, we developed and optimized a novel cationic-ionizable lipid nanoparticle platform, QTPlus, for the co-delivery of DOX and siRNA targeting fibroblast growth factor 2 (siFGF2). Methods: The study evaluated the physicochemical properties, cellular uptake, gene regulation, apoptosis induction, and in vivo antitumor efficacy and safety of QTPlus-DOX-siFGF2 in breast cancer models. Results: QTPlus nanoparticles based on the A-066 formulation achieved uniform particle size (~218 nm), low polydispersity (PDI 0.164–0.214), and high encapsulation efficiencies (DOX: 49.56 ± 0.15%; siFGF2: 77.66 ± 1.30%). In vitro release studies revealed a robust pH-responsive profile, characterized by sustained stability at physiological pH (7.4) and rapid burst release at acidic endosomal pH (5.5). In MCF-7 and MDA-MB-231 cells, QTPlus-DOX-siFGF2 significantly enhanced cellular uptake, downregulated FGF2 (0.639-fold) and VIM (0.373-fold), and upregulated CASP3 (3.364-fold in siFGF2 group) and BRCA1 (4.041-fold). Flow cytometry showed markedly increased apoptosis (78.5% vs. 42.65% for QTPlus-DOX alone). In the MDA-MB-231 xenograft model, QTPlus-DOX-siFGF2 achieved 65.87% tumor growth inhibition with stable body weights and favorable trends in cardiotoxic biomarkers. Conclusions: These results demonstrate that QTPlus enables effective co-delivery of DOX and siFGF2, producing synergistic antitumor effects through apoptosis induction and suppression of epithelial–mesenchymal transition while improving the safety profile. QTPlus-DOX-siFGF2 represents a promising nanotherapeutic strategy for breast cancer warranting further clinical development.