Lipid nanoparticle-based multi-scale systemic immune programming for cancer therapy

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 chimeric antigen receptor T cell (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 immunometabolic disorder rather than a localized disease.