Polysaccharide Nanoadjuvants Engineered via Phenotype-Specific Nanoprobe-Assisted Phenotypic Screen Reprogram Macrophage Cell Functions for Cancer and Rheumatoid Arthritis Therapy

Macrophage plays critical roles in immune-related diseases, acting as a crucial therapeutic target for immunotherapy. Rational design and development of effective therapeutics for macrophage reprogramming are still challenging. Here, we rationally engineered polysaccharide nanoadjuvants to reprogram macrophage functions for enhanced immunotherapy in multiple diseases through a macrophage phenotype-specific nanoprobe (MPSNPr)-assisted high-throughput phenotypic screen. This MPSNPr exhibited high macrophage M1 phenotype specificity because of the formation of H-aggregates on the outer surface and the binding to glucose transporter 1 receptors by the polysaccharide nanocarrier. Based on this MPSNPr, a high-throughput platform was constructed and employed to screen a variety of pharmaceuticals for macrophage reprogramming, being able to identify both pro-inflammatory and anti-inflammatory drug candidates. Polysaccharide nanoadjuvants, Dex-BA and Dex-SAL, were rationally engineered with two potent candidates to amplify macrophage reprogramming efficacy both in vitro and in vivo. Dex-BA significantly inhibited tumor growth by inducing macrophage M1 polarization, dendritic cell maturation, and cytotoxic T cell activation in a mice melanoma model. Dex-SAL alleviated rheumatoid arthritis symptoms with reduced inflammation by reprogramming activated macrophages toward anti-inflammatory phenotype. Our work provides a robust strategy for the rational design and development of effective therapeutics for enhanced macrophage-mediated immunotherapy in diverse diseases.