Synergistic Effects of Functionalized Liquid-Metal Nanoparticles in Anti-inflammation and Targeted Photothermal Therapy of Breast Cancer

Chronic inflammation plays a critical role in breast cancer progression by promoting immune suppression, angiogenesis, and metastasis. However, conventional therapies often fail to address this inflammatory microenvironment and may even intensify it, limiting treatment efficacy. This study aims to develop stable liquid-metal eutectic gallium-indium (EGaIn) nanoparticles modified with 4-nitrobenzenediazonium tetrafluoroborate (4NT) which was then further modified with gold nanoparticles (Au) and folic acid (FA) to achieve EGaIn-4NT@Au-FA nanoparticles. With anti-inflammatory property, EGaIn-4NT@Au-FA demonstrated synergistic breast cancer treatment through Au-mediated photothermal therapy (PTT) and folate-targeted delivery. These nanoparticles exhibited approximately 50% uptake by MDA-MB-231 breast cancer cells and reduced their viability to below 30% under 808 nm laser irradiation. A single intravenous injection of EGaIn-4NT@Au-FA followed by laser exposure elevated tumor temperatures to ∼85 °C in BALB/c nude mice, resulting in significant tumor growth inhibition <i>in vivo</i>. Tumor growth in treated mice was inhibited by around 50% by day 12 compared to controls, and PCNA-positive proliferative cell rates dropped from 91.86% to 10.65% by day 3. Serum analysis also showed marked reductions in inflammatory cytokines shortly after treatment, indicating systemic immunomodulation. FA modification enhanced nanoparticle accumulation in tumors via receptor-mediated endocytosis, improving therapeutic precision and minimizing off-target effects. In this design, 4NT functions as a multifunctional surface modifier that refines the particle size, hydrophilicity, and colloidal stability of EGaIn nanoparticles. After nitro-to-amine conversion, the 4NT layer also provides reactive anchors for dense Au deposition and subsequent FA conjugation. An EGaIn-4NT@Au-FA-based multifunctional nanoplatform, as an effective nanomedicine, enables efficient integration of targeting, photothermal, and anti-inflammatory functions within a single nanoplatform.