Circulating cell-free DNA (cfDNA) released by damaged cells causes inflammation and has been associated with the progression of sepsis. One proposed strategy to treat sepsis is to scavenge this inflammatory circulating cfDNA. Here, we develop a cfDNA-scavenging nanoparticle (NP) that consists of cationic polyethylenimine (PEI) of different molecular weight grafted to zeolitic imidazolate framework-8 (PEI-g-ZIF) in a simple one-pot process. PEI-g-ZIF NPs fabricated using PEI 1800 and PEI 25k but not PEI 600 suppressed cfDNA-induced TLR activation and subsequent nuclear factor kappa B pathway activity. PEI 1800-g-ZIF NPs showed greater inhibition of cfDNA-associated inflammation and multiple organ injury than naked PEI 1800 (lacking ZIF), and had greater therapeutic efficacy in treating sepsis. These results indicate that PEI-g-ZIF NPs acts as a “nanotrap” that improves upon naked PEI in scavenging circulating cfDNA, reducing inflammation, and reversing the progression of sepsis, thus providing a novel strategy for sepsis treatment.

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Radiotherapy is essential for treating unresectable or metastatic breast cancer, but radiotherapy-induced tumor cell death generates small extracellular vesicles (sEVs) that promote tumor regrowth and metastasis following treatment. Here cationic nanosheets with a high sEVs-binding capacity that suppress sEVs-induced tumor regrowth and metastasis following radiotherapy is developed. Molybdenum disulfide (MoS 2 ) monolayers are prepared by using lithium ions as intercalation agents, and are functionalized with cationic polyamidoamine (PAMAM) dendrimers. The MoS 2 -PAMAM particles exhibit a corrugated sheet-like nanostructure with a larger surface-to-volume ratio than spherical PAMAM-functionalized particles, resulting in greater sEVs binding capacity. Treatment of MDA-MB-231 human breast cancer cells with the MoS 2 -PAMAM nanosheets reduces sEVs-induced Toll-like receptor activation and tumor cell proliferation, migration, and invasion to a greater extent than treatment with spherical PAMAM nanoparticles. In a mouse 4T1 metastatic breast cancer model, the nanosheets exhibit greater inhibition of tumor regrowth and metastasis after radiotherapy than the spherical nanoparticles, demonstrating the potential of these sEVs-scavenging nanosheets for improving outcomes for breast cancer radiotherapy patients. The work reveals a pivotal role of the 2D sheet-like materials in binding sEVs, indicating the significance of nanoscale geometry in developing the next-generation sEVs-scavenging biomaterials.