Nanoparticle-Mediated PPAR Modulation of Macrophage Polarization in Radiation Enteritis: A Narrative Review

Abstract: Radiation enteritis (RE) is a frequent and clinically important adverse effect of abdominal radiotherapy, characterized by acute inflammatory injury and longer-term fibrotic remodeling of the intestinal tract. Most patients receiving pelvic or abdominal irradiation experience measurable worsening of intestinal function. Macrophages orchestrate RE pathogenesis: tissue injury initially triggers a pro-inflammatory M1 phase that amplifies damage, followed by an M2 phase that promotes repair. Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of macrophage polarization, with PPARγ playing a prominent role in promoting anti-inflammatory and tissue-restorative responses. This review explores the molecular mechanisms linking macrophage polarization and PPAR signaling in RE, reviews current PPAR-targeted therapies, and describes nanotechnology-based strategies for targeted intestinal delivery of PPAR modulators. We discuss how PPAR agonists modulate immune responses and how formulations engineered for localized intestinal activity may reduce systemic adverse effects. We also highlight progress in nanoparticle design, including carriers responsive to pH or reactive oxygen species and ligand-coated systems (e.g. hyaluronic acid or mannose) that target macrophages, thereby enhancing therapeutic delivery and cellular uptake. Finally, we summarize emerging omics-based approaches (single-cell transcriptomics, spatial profiling, and artificial-intelligence-driven design) that are accelerating the identification of novel therapeutic targets and informing the development of precision nanomedicines for RE. Keywords: radiation enteritis, PPAR, macrophage, nanoparticle drug delivery, targeted nanotherapy