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We've published work in Advanced Functional Materials on heparin-folate nanoparticles (HF NPs) as a way to unlock heparin's anticancer potential without the bleeding risk that has always prevented clinical use. Heparin is best known as an anticoagulant, but it also has real immunomodulatory and anti-angiogenic activity through neutrophil activation, complement regulation, and VEGF neutralization. The problem has been that the doses needed to exploit those effects would cause dangerous bleeding, and chemically chopping heparin into low-molecular-weight forms only partly solves it.

We demonstrate a structural solution to this problem by creating heparin-folate conjugates which self-assemble into a 3D nanoparticle. This 3D assembly buries the antithrombin-binding pentasaccharide so it can no longer bridge antithrombin and thrombin, while leaving the less sequence-specific VEGF and growth-factor binding capabilities intact. The result cuts anticoagulant activity roughly 15-fold versus unfractionated heparin and opens a bleed-free window up to 160 mg/kg, a dose that would be lethal for ordinary heparin. As a monotherapy in mouse melanoma models, HF NPs reduced lung metastasis by 76%, remodeled tumor vasculature toward a more normal architecture, and suppressed primary tumor growth, all without the direct cytotoxicity you would expect from a conventional drug.


The most striking result came from asking whether HF NPs could sensitize tumors to checkpoint blockade through pathways that don't depend on T cells. We used a T-cell-deficient xenograft, a setting where anti-PD-1 is expected to underperform. Anti-PD-1 or HF NPs alone inhibited tumor growth by ≤60%, but the combination drove 98.9% regression, with tumors disappearing entirely in several animals. Transcriptomic profiling of treated endothelial cells backed this up, showing enrichment of innate immune and checkpoint-related signaling alongside the expected VEGF suppression. Taken together, the work shows that anticoagulation-silent heparin can safely engage the innate immune and vascular arms that both heparin and checkpoint inhibitors quietly rely on, arms that are established in each but understudied as synergistic targets.


Preprint and fulltext links available here.