Liposomal Nanoparticle Mediated Chemo-Phototherapy for Breast Cancer Ablation via Boldine Driven Metabolic Reprogramming.

Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive phenotype, molecular heterogeneity, and lack of specific therapeutic targets. To address these limitations and align with emerging personalized medicine strategies, a multifunctional liposomal nanocarrier (RELIB) was developed to co-encapsulate the chemotherapeutic alkaloid Boldine and the near-infrared (NIR)-responsive photothermal dye IR775, enabling combined chemo-photothermal therapy with tunable therapeutic potential. RELIB nanoparticles (RELIB NPs) (∼200 nm) demonstrated high encapsulation efficiency and effective photothermal conversion under NIR irradiation. In vitro studies in 4T1 cells revealed enhanced cellular internalization, selective cytotoxicity, induction of apoptosis, mitochondrial membrane depolarization, DNA damage, and inhibition of migration and clonogenic survival. Importantly, RELIB exhibited favorable biocompatibility in Zebrafish and Drosophila melanogaster models. In vivo evaluation in 4T1 tumor-bearing mice showed significant tumor regression upon NIR irradiation, with minimal systemic toxicity. Metabolomic profiling further indicated reprogramming of key pathways involved in apoptotic signaling and tumor suppression, suggesting the potential to use metabolic signatures to guide treatment response. Notably, Boldine conferred cyto-protection in normal cells, preserving cellular homeostasis and highlighting the platform's selective targeting capacity. Collectively, these findings position RELIB as a promising, biocompatible, and adaptable nanotherapeutic system with strong potential for personalized intervention in TNBC.