Supramolecular self-assembly of multifunctional carrageenan-based Nanomicelles for effective tumor therapy via apoptosis and immunogenic cell death

Combination therapy that promotes both apoptosis and immunogenic cell death (ICD) holds promise for enhanced tumor treatment, yet its effectiveness is often hindered by challenges including inadequate targeted delivery, intricate nanoformulations processes, and cost inefficiency. Here, we present novel tumor-targeted, stimuli-responsive nanomicelles (D@CGO-G) through a straightforward supramolecular self-assembly method, incorporating targeting peptide GE11, doxorubicin (DOX), and a labile carrageenan (CG) linkage. Mechanistic insights into nanomicelles assembly process are thoroughly investigated using molecular dynamics (MD) simulations. D@CGO-G exhibit superior targeting capability both in vitro and in vivo , while the released DOX induces tumors apoptosis and ICD, stimulating macrophage polarization and enhancing the infiltration of tumor cytotoxic T lymphocytes. Furthermore, D@CGO-G effectively suppress both primary and distant tumors in vivo through combined apoptosis and anti-tumor immune responses. Our results highlight a simple, cost-effective approach to develop responsive CG-based nanomicelles for precise tumor targeting and robust multimodal therapeutic effects, advancing their clinical potential in cancer therapy.