Metabolic reprogramming targeting the mevalonate pathway represents an emerging innate immune activation target. However, its regulatory mechanisms remain incompletely elucidated. Here, we target the mevalonate pathway and construct a nano-granulated zoledronate (Nano-ZD) modulator. Following subcutaneous injection, Nano-ZD preferentially accumulates in draining lymph nodes rather than in bone tissues, enabling targeted delivery to innate immune cells. Nano-ZD functions as an immune-metabolic adjuvant, sensitizing and amplifying immune responses. By integrating Nano-ZD with the TLR4 agonist monophosphoryl lipid A (MPLA), MPLA-loaded Nano-ZD (Nano-ZDM) elicits robust humoral and antitumor cellular immunity. Mechanistically, Nano-ZD not only inhibits the isoprenylation of RhoA GTPases but also reduces coenzyme Q (CoQ) biosynthesis. CoQ deficiency disrupts oxidative phosphorylation (OXPHOS) and pyrimidine metabolism, causes mitochondrial ROS accumulation, induces mitochondrial antiviral protein (MAVS) oligomerization, and activates the pyrin inflammasome. This mevalonate-CoQ-OXPHOS/pyrimidine metabolism axis serves as a promising target for screening additional immune-metabolic adjuvants, and nanofabrication offers a paradigm for the lymph-targeted in vivo delivery of such adjuvants.
Chen et al. (Wed,) studied this question.