Systematic discovery of immunomodulatory plant-derived nanoparticles reveals RNA-mediated macrophage reprogramming

Plant-derived nanoparticles (PNPs) have emerged as a promising class of bioactive nanomaterials with intrinsic immunomodulatory properties, offering a sustainable and biocompatible alternative to synthetic delivery systems. However, their systematic exploration has been hindered by a fragmented "one-plant-one-function" research paradigm. Here, we establish a comprehensive bio-discovery platform by constructing a taxonomically diverse library of 110 PNPs. Through integrated physicochemical characterization and high-throughput functional screening, we identify Allium tuberosum-derived nanoparticles (ANPs) as a potent bioactive nanoparticle that effectively promotes pro-inflammatory macrophage polarization. Mechanistically, we demonstrate that the bioactivity of ANPs is largely mediated by their endogenous RNA cargo, specifically ANP-miR-488, which modulates the Bcl6 signaling axis to initiate macrophage reprogramming. Furthermore, ANPs significantly sensitize cold tumors to immune checkpoint blockade therapy in a syngeneic LLC1 lung carcinoma model. This study not only provides a generalizable strategy for the systematic discovery of bioactive nanomaterials but also highlights the clinical potential of RNA-mediated PNPs as a promising platform for enhancing cancer immunotherapy.