Mycobacterium tuberculosis-induced PCBP1 degradation drives macrophage ferroptosis to promote infection: a lung-macrophage-targeted RNAa nanotherapy

BACKGROUND: Immune evasion by Mycobacterium tuberculosis (Mtb) complicates tuberculosis (TB) therapy. Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a critical process in host-pathogen interactions. We aimed to define the role of poly(C)-binding protein 1 (PCBP1) in macrophage ferroptosis during Mtb infection and to develop a targeted RNA activation (RNAa) nanotherapy to exploit this pathway. METHODS: We analyzed clinical samples from TB patients and investigated Mtb-host interactions in macrophage models using molecular and biochemical assays. Mannosylated lipid nanoparticles (MLNPs) were engineered to deliver PCBP1-targeting small activating RNAs (saRNAs). Therapeutic efficacy, lung-specific delivery, and biocompatibility were evaluated in a murine TB model. RESULTS: Mtb utilizes the host E3 ubiquitin ligase Trim21 to mediate the proteasomal degradation of PCBP1. PCBP1 loss induced macrophage ferroptosis by modulating its downstream targets GPX4, PTGS2, and HMOX1, promoting bacterial survival. In vitro, saPCBP1@MLNPs restored PCBP1 expression, reversed ferroptosis markers (Fe²⁺, 4-HNE), and reduced Mtb burden. In murine models, the nanotherapy achieved lung-specific delivery, significantly attenuated lung pathology, and enhanced bacterial clearance. CONCLUSIONS: PCBP1 is a critical, druggable immune-metabolic checkpoint that governs macrophage ferroptosis in TB. Our targeted RNAa nanotherapy represents a promising host-directed strategy for Mtb infection, linking a key molecular mechanism to a translational therapeutic platform and offering a new approach for treating drug-resistant TB.