Triple negative breast cancer revolution has identified a plethora of therapeutic targets making it apparent that a single target for its treatment could be rare hence creating an urge to develop robust technologies for combination drug therapy. Paclitaxel, hailed as the most significant advancement in chemotherapy faces several underpinnings due to its low solubility and permeability. Advancing research has demonstrated the role of interferons in cancer. DEAE-Dextran, an emerging molecule with evidence of interferon induction was utilized in the present study to develop a nanoformulation in conjugation with paclitaxel to target multiple therapeutic pathways, with diminution of paclitaxel adverse effects and develop a specific targeted nano system. Evidently, it was demonstrated that DEAE-Dextran coated nanoformulation portrays significant synergistic cytotoxicity in the various cell lines. Moreover, overcoming the activation of ROS by paclitaxel, the combination drug therapy more effectively inhibited ROS through β-interferon induction. The nanoformulation was further conjugated to FITC for internalization studies which subsequently indicated maximum cellular uptake at 60 min post treatment demonstrated by green fluorescence from FITC lighting up the nuclear membrane. Precisely, the mechanistic approach of nuclear-targeted nanoformulation was evaluated by in vivo xenograft studies which showed a synergistic release of β-interferon at the target organ. Moreover, the combination nanoformulation inculcated multiple mechanistic approaches through VEGF and NOTCH1 inhibition along with dual β and γ-interferon overexpression. Overall, the combination therapy may be a promising multifunctional nanomaterial for intranuclear drug delivery in TNBC.