Concurrent P-Selectin Targeting Nanoparticle Orchestrates Tumor-Immune Dynamics for Advanced Immunochemotherapy.

Abstract

Cancer therapy is often constrained by targeting single pathogenic mechanisms without addressing the complex tumor microenvironment (TME). Here, we introduce FINAL (Fucoidan-docetaxel Immunomodulatory Nanoparticles as an Antitumoral Lancer), a surface-engineered nanoplatform that simultaneously targets P-selectin-expressing cancer cells and tumor-associated macrophages (TAMs). Beyond targeting specificity, fucoidan surface modification provides intrinsic bioactivities that individually modulate both cell types while coordinately reshaping the TME. FINAL achieves dual-cell orchestration through P-selectin-mediated targeting, activating both receptor-dependent signaling pathways and receptor-independent bioactivities of fucoidan and DTX. P-selectin-mediated targeting enhances cellular uptake and disrupts tumor-TAM adhesion, reducing the level of circulating hybrid cell (CHC) formation. Independent of targeting, fucoidan's bioactivity reduces cellular reactive oxygen species in cancer cells, promotes M1 macrophage polarization, and suppresses VEGF-A-mediated angiogenesis. RNA-seq transcriptomic profiling demonstrated that FINAL drives synergistic immune activation pathways while simultaneously repressing tumor progression signatures, providing mechanistic evidence for concurrent tumor-immune dynamics at the molecular level. In triple-negative breast cancer (TNBC) models, this system-level approach achieved breakthrough therapeutic outcomes, including doubling survival duration, suppressing primary tumor growth, inhibiting lung metastasis, and preserving bone marrow hematopoietic function, demonstrating translational potential compared to conventional docetaxel formulations. Importantly, FINAL maintained therapeutic benefits while reducing systemic toxicity, establishing an optimal balance between antitumor efficacy and safety. The rationally designed fucoidan nanobio interface establishes FINAL as a versatile platform for P-selectin-expressing diseases for next-generation immunochemotherapy agents with broad translational potential across multiple cancer types.