In Situ Red Blood Cell Hitchhiking Nanoparticles for Lung‐Selective Immune Reprogramming

ABSTRACT Premature clearance and limited organ targeting remain major barriers for nanoparticle (NP) drug delivery. Hitchhiking NPs on red blood cells (RBCs) can enhance circulation and organ‐selective accumulation, but most approaches require ex vivo RBC extraction and reinfusion, limiting clinical translation. Here, we report an in situ RBC‐hitchhiking strategy, named i‐Bind, which employs polyphenol surface functionalization to enable spontaneous NP attachment to RBCs directly in the bloodstream. Driven by strong interactions of phenolic motifs with RBC membranes, i‐Bind NPs exhibited markedly enhanced and more stable hitchhiking onto RBCs under flowing whole blood conditions. In both healthy and diseased mice, i‐Bind NPs preferentially target the lungs, resulting in an over 20‐fold increase in lung‐to‐liver deposition ratio compared to unmodified NPs. Additionally, i‐Bind NPs show preferential targeting to distinct lung immune cell subsets in a pathology‐dependent manner, including cDC2s in healthy lungs, neutrophils in acute lung injury, and cDC1s in lung metastases. In a melanoma lung metastasis model, delivery of the STING agonist diABZI via i‐Bind NPs significantly inhibited lung metastasis progression by reprogramming the lung immune microenvironment. Collectively, i‐Bind provides a simple and versatile platform for organ‐targeted drug delivery and immune reprogramming.