Nano-granulated zoledronate sensitizes innate immune metabolism to enhance vaccine-induced and antitumor immunity.
basic_science · Level V
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- Record sourced from PubMed, PMID 42025165.
- Also identified by DOI 10.1016/j.xcrm.2026.102765.
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Abstract
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.