Anticoagulation‐Silent Heparin Nanoparticles Enable Innate Immune Activation and Non‐T‐Cell Synergy With Checkpoint Blockade

Heparin demonstrates potent innate immunomodulatory activity through neutrophil activation, complement regulation, and VEGF neutralization, but its therapeutic potential in cancer has been precluded by severe bleeding risk from anticoagulant activity. Here, we developed anticoagulation‐silent heparin‐folate nanoparticles (HF NPs) through controlled 3D self‐assembly that likely reduces accessibility of the antithrombin‐binding pentasaccharide while preserving innate immune and growth factor binding functions. HF NPs exhibited ∼15‐fold reduced anticoagulation versus unfractionated heparin with a bleed‐free safety window up to 160 mg kg − 1 . In mouse melanoma models, HF NPs monotherapy reduced lung metastasis by 76% and inhibited primary tumor growth. In vitro transcriptomic analysis suggested broad immune signaling pathway enrichment alongside vascular remodeling and VEGF pathway suppression, consistent with innate immune engagement. To examine checkpoint responses in a T‐cell‐deficient context, we used a T‐cell‐deficient xenograft model where aPD‐1 or HF NPs alone produced ≤60% tumor inhibition, whereas combination therapy yielded 98.9% regression with complete tumor disappearance in multiple mice. These findings demonstrate that anticoagulation‐silent HF NPs enable safe engagement of heparin's innate immune and vascular activities to sensitize tumors to checkpoint blockade in a T‐cell‐deficient setting.