pH-Sensitive Niosomal Nanoencapsulation of Beta-Caryophyllene and its Novel Pathway in Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive malignancy requiring innovative therapies. This study aimed to develop a pH-sensitive hybrid niosomal beta-caryophyllene (BCP) formulation to overcome its delivery limitations and leverage a novel anticancer pathway using in silico tools. Using in silico methods, HSP90AA1 was identified as a key TNBC target, with network pharmacology, molecular docking, and dynamics confirming the stable binding of BCP. Hybrid niosomes were prepared via a thin-film hydration method with PLGA modification to enhance pH-sensitive delivery. The formulations were characterized for particle size, encapsulation efficiency, and drug release profiles, while cytotoxicity was evaluated using the CCK-8 assay in 4T1 TNBC cells. PLGA-modified niosomes achieved a particle size of 187.6 ± 7.82 nm, 91.96 ± 2.71% encapsulation efficiency, and exhibited pH-responsive release, significantly increasing BCP release at pH 5.5 compared to pH 7.4. The hybrid formulation demonstrated superior cytotoxicity (IC50: 15.65 ± 6.19 µg/mL), representing a 4.61-fold improvement compared to free BCP and a 1.96-fold enhancement over standard niosomes. Leveraging the novel BCP-HSP90AA1 pathway enhanced anticancer efficacy, showcasing a promising strategy for TNBC treatment. This study integrates computational and experimental approaches to address BCP’s delivery challenges, highlighting the potential of PLGA-modified niosomes as a targeted TNBC therapy.