Exosome Platform with Three-in-One Functionality of mRNA Therapy, Immune Checkpoint Blockade, and Mild Photothermal Therapy for the Treatment of Triple-Negative Breast Cancer

Immune checkpoint blockade (ICB) has shown promising potential for treating triple-negative breast cancer (TNBC), but its efficacy is limited, mainly due to the "cold," suppressive immune tumor microenvironment (TME). Therefore, improving the TME is crucial for enhancing therapeutic effects against TNBC. Here, we presented a multifunctional nanotherapeutic platform (ALEvs@LNPs) designed to combine cytokine-sensitized mild photothermal therapy, ICB, and interleukin-2 (IL2) mRNA therapy to reprogram the TME, thereby improving the efficacy of ICB therapy in TNBC. Tumor cell-derived exosome-camouflaged lipid nanoparticles with antilymphocyte activation gene-3 (LAG3) were developed to codeliver the photothermal agent IR806, IL2 mRNA, and LAG3 inhibitory antibody (anti-LAG3). Mild photothermal therapy facilitated the reprogramming of "cold" tumors into "hot," thereby enhancing the therapeutic effects of ICB. Meanwhile, ICB also promoted cytokine secretion, increasing the sensitivity of tumor cells to heat. Additionally, IL2 mRNA therapy induced T-cell proliferation and activation, further augmenting the efficacy of ICB. Together, these three therapies established a positive feedback loop that enhanced the therapeutic effects of ICB. This multifunctional nanotherapeutic platform effectively reprogrammed the "cold," suppressive immune TME, offering a promising strategy for TNBC treatment.