Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, making traditional hormone and targeted therapies ineffective. Chemotherapy remains the primary treatment for TNBC; however, it has failed to adequately address the high rates of recurrence and metastasis, underscoring the urgent need for new therapeutic strategies. This study investigates Saikosaponin A (SSA), a compound extracted from traditional Chinese medicine, for its potential to enhance the efficacy of doxorubicin (DOX) chemotherapy while reducing TNBC metastasis and mitigating DOX-induced cardiotoxicity. We first confirmed SSA's cardioprotective effects against DOX-induced cardiotoxicity, highlighting its potential as an adjunctive therapy for TNBC chemotherapy. Subsequently, through network pharmacology analysis, we identified that SSA may inhibit TNBC progression and metastasis by downregulating integrin β3, a key regulatory factor in tumor development. This was further validated through both in vivo and in vitro experiments. To address the poor bioavailability of SSA, we developed a novel drug delivery system utilizing hyaluronic acid (HA)-modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles for the co-delivery of SSA and DOX. This nano-drug system exhibited excellent stability and high drug-loading capacity, with loading efficiencies of 40.07 % for SSA and 43.07 % for DOX. After 24 h of nano-drug administration, the DOX concentration in the group using the nano-delivery system was 5.01 times higher than control group, demonstrated enhanced tumor-targeting capability. Furthermore, after 14 days of treatment, the tumor volume was reduced by 80.8 % compared to the control group, indicating significantly improved therapeutic efficacy (all P < 0.05). This study systematically evaluates the potential of this dual drug-loaded nanocarrier in improving TNBC treatment, reducing DOX-induced cardiotoxicity, and inhibiting metastasis, offering a novel therapeutic approach that integrates traditional medicine with advanced nanotechnology.Copyright © 2024 Elsevier B.V. All rights reserved.