Extracellular targeted protein degradation is an emerging therapeutic strategy but has been rarely explored for clearing circulating pathogenic mediators. Here we report stiffness-oriented lysosome self-sorting nanodegraders (SOLIDs) for hepatic lysosomal degradation of serum immune mediators. SOLIDs feature a rigid semiconducting polymer core that is revealed for the first time to confer near-quantitative lysosomal accumulation across diverse cell types. After surface bioconjugation, SOLIDs capture the immune mediators of interest from blood via controlled protein corona formation. The resulting corona composition directs biodistribution, producing predominant accumulation in the liver, where they get degraded in hepatic lysosomes. We show that IL-6-capturing SOLIDs reduced serum IL-6 by an additional 70% versus IL-6 antibody therapy and increased 7-day survival in a murine sepsis model from 0% to 66.7%. In an acute lung injury model, CpG-capturing SOLIDs reduced pulmonary immune cell infiltration 1.7-fold relative to CpG neutralization and suppressed expression of co-stimulatory molecules. This work identifies nanoparticle mechanics as a critical factor in organelle targeting and proposes a nano-therapeutic approach for the degradation of pathogenic serum biomolecules.