Engineering biodegradable lipid nanoparticles with endo-lysosomal escape capability for chronological therapeutic immunomodulation to enhance interleukin-15 therapy.

Interleukin-15 (IL-15) has emerged as a compelling immunostimulatory cytokine for the treatment of refractory, metastatic, and recurrent triple-negative breast cancer (TNBC). However, the crosstalk between tumor cells and M2-type tumor-associated macrophages (M2-TAMs) might lead to IL-15 sequestration, ultimately inducing resistance to IL-15 therapy in TNBC. Resiquimod (R848), a Toll-like receptor 7/8 (TLR7/8) agonist, promotes M2-to-M1 repolarization of TAMs, thereby remodeling the immunosuppressive tumor immune microenvironment (TIME). Herein, biotin-targeted, biodegradable fluorinated lipid nanoparticles (LNPs) are fabricated for compartmentalized encapsulation of IL-15 messenger RNA (IL-15 mRNA) and R848 for chronological TLR-augmented cytokine immunotherapy (TACIT), which acts through tumor immune landscape remodeling. Owing to outside-in degradation of the diselenide-bridged LNPs in the redox environment, R848 is rapidly released and transported into the extracellular space to reprogram M2-to-M1 macrophages, disrupting the inhibitory crosstalk of macrophages with tumor cells and reducing IL-15 sequestration. Subsequently, IL-15 mRNA is released to trigger sustained IL-15 expression and secretion through intracellular translation, which initiates immune responses to inhibit tumor growth. Importantly, this chronological TACIT strategy demonstrates potent antitumor efficacy in vivo across multiple TNBC models. This tailor-designed multifunctional LNP offers a pioneering avenue for advancing chronological TACIT-based treatments against TNBC by enhancing IL-15 therapy.