Lenalidomide-utilizing self-assembled immunogenic cell death-inducing heparin/doxorubicin nanocomplex for anticancer immunotherapy

Abstract

Lenalidomide (LEN), a thalidomide analogue widely used in the treatment of multiple myeloma, has had limited application in other cancer therapies due to challenges such as its immune-based cytotoxic limitations, low efficacy in solid tumors, and the risk of thrombosis. To overcome these hurdles, we developed a novel self-assembling immunogenic nanocomplex that combines lenalidomide with unfractionated heparin (UFH), a highly negatively charged anticoagulant, and doxorubicin (DOX), a potent cytotoxic agent. The nanocomplex is formed through charge-charge and hydrophobic interactions, resulting in a self-assembled UFH/DOX/LEN complex (HepDL) that generates nanoparticles approximately 140 nm in size in saline. Molecular dynamics (MD) simulations confirmed the formation process of the HepDL nanocomplex. These carrier-free, drug-only nanoparticles induce immunogenic cell death (ICD) by releasing DOX in a controlled manner, thereby activating CD8+ T cells, natural killer (NK) cells, natural killer T (NKT) cells, and dendritic cells (DCs). This leads to enhanced anti-tumor efficacy in the CT26.CL25 tumor model, demonstrating a robust immune-boosting effect. This study presents a significant advancement in the development of immunogenic nanoparticles incorporating lenalidomide for cancer treatment. © 2025 Elsevier Ltd