The clinical reach of cancer immunotherapy is currently limited by off-target toxicity, physical barriers in solid tumors, and the complex manufacturing of personalized cell therapies. This review presents multi-scale systemic immune programming as a transformative approach, in which lipid nanoparticles (LNPs) function not merely as delivery vehicles but as programmable platforms that direct immune responses across biological scales. At the molecular and cellular levels, LNP design and intracellular delivery regulate mRNA stability, translation, and antigen presentation. At the tissue level, intratumoral mRNA delivery reprograms the tumor microenvironment to overcome stromal barriers and immunosuppression. At the systemic level, LNPs coordinate immune responses, including in vivo CAR-T engineering and vaccine-driven immune memory. At the organismal level, liver-targeted LNPs restore metabolic regulators, reverse cachexia, and improve host resilience. Building on this framework, we propose a dual-track therapeutic paradigm that integrates tumor-directed immune activation with host physiological restoration. Together, this approach positions LNP-based therapies to treat cancer as a systemic immune-metabolic disorder rather than a localized disease.
Suppressor transfer RNAs (sup-tRNAs) can rescue disease-causing nonsense mutations by promoting readthrough of premature termination codons (PTCs). Their clinical translation is limited by suboptimal activity and inefficient in vivo delivery. In this work, we combined site-specific chemical modification of sup-tRNAs with cargo-tailored pulmonary lipid nanoparticle (LNP) engineering to overcome these barriers. Incorporation of N1-methyladenosine in sup-tRNAs improved PTC readthrough, enhanced tRNA aminoacylation, prolonged functional persistence, and reduced innate immune activation. High-throughput ionizable lipid screening and formulation optimization identified a sup-tRNA-tailored LNP that efficiently delivered chemically modified sup-tRNAs to the lung. This approach restored cystic fibrosis transmembrane conductance regulator (CFTR) expression and function in bronchial epithelial cells, mouse models, and patient-derived organoids. Thus, LNP-delivered, chemically engineered sup-tRNAs represent a potential therapeutic platform for treating nonsense mutations.
This study provides direct evidence that VEXAS-specific TE govern HSC clonal dominance, thereby uncovering a regulatory axis underlying HSC biology and disease mechanisms, opening a therapeutic strategy directed towards the repetitive genome.
A. Varesi, Sontago Dong, Chiara Gaddoni et al.· bioRxiv· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
