Interleukin 15‐Presenting Nanovesicles with Doxorubicin‐Loaded Ferritin Cores for Cancer Immunochemotherapy

Abstract Interleukin 15 (IL15) is crucial for fostering the survival and proliferation of nature killer (NK) cells and cytotoxic T lymphocytes (CTLs), playing a pivotal role in tumor control. However, IL15 supplementary therapy encounters challenges such as systemic inflammation and non‐specific stimulation of cancer cells. Herein, a nanovesicle termed DoxFILN, comprising a membrane presenting IL15/IL15 receptor α complexes (IL15c) and a core of doxorubicin‐loaded ferritin (Dox‐Fn) are reported. The DoxFILN significantly enhances the densities and activities of intratumoral CTLs and NK cells. Mechanistically, DoxFILN undergoes deshelling in the acidic tumor microenvironment, releasing Dox‐Fn and membrane‐bound IL15c. Dox‐Fn selectively target transferrin receptors on cancerous cells, facilitating intracellular Dox release and inducing immunogenic cell death. Concurrently, membrane‐bound IL15c recognizes and activates IL15 receptor β/γc heterodimers, leading to a remarkable increase in the proliferation and activation of CTLs (16‐fold and 28‐fold) and NK cells (37‐fold and 50‐fold). The IL15‐displaying nanovesicle introduced here holds promise as a potential platform for immunochemotherapy in the treatment of cancer.