Cocktail-like alginate-derived carbonized nanogels with diverse moieties attenuate tumor metastasis via potential multi-pathway modulation

Abstract

Carbonized nanomaterials possess diverse functional moieties that complicate biomedical use but also confer multi-target therapeutic potential. Here, carbonized nanogels (CNGs) were synthesized from sodium alginate (Alg) via mild pyrolysis, yielding ultrasmall graphene-like domains embedded in a crosslinked nanogel matrix enriched with bioactive moieties. These features endowed Alg-CNGs with antioxidative, anti-inflammatory, and membrane-perturbing properties, enabling modulation of cellular signaling relevant to cancer progression. In vitro, Alg-CNGs suppressed epithelial-mesenchymal transition in 4T1 triple-negative breast cancer cells by increasing E-cadherin and decreasing N-cadherin and vimentin, thereby attenuating EMT-associated motility as evidenced by reduced migration/invasion and marked perturbation of actin organization and adhesion-related dynamics. Quantitative proteomics coupled with Ingenuity Pathway Analysis further indicated attenuation of metastasis-associated networks, including RhoA/Rac1/Cdc42-integrin signaling and PI3K/AKT, PTEN, and ERK/ MAPK pathways. In an orthotopic breast cancer model, Alg-CNGs accumulated selectively in tumors and reduced pulmonary metastasis by 90% without systemic toxicity. Structure-function analysis indicated that phenolic, lactone, and quinone moieties on the CNGs may contribute to regulating oxidative stress, actin remodeling, and receptor-mediated signaling. These findings demonstrate that Alg-CNGs exert cocktail-like" multifunctional actions