DNASE1

Overview

Deoxyribonuclease I (DNase I), encoded by the DNASE1 gene, is an endonuclease that catalyzes the hydrolytic cleavage of phosphodiester bonds in the DNA backbone, generating oligonucleotides with free 3'-hydroxyl and 5'-phosphate termini. It is expressed in numerous tissues and is secreted into body fluids including serum, urine, and pancreatic secretions, where it serves a homeostatic role in clearing extracellular DNA (cf-DNA) and chromatin-based structures. DNase I preferentially cleaves double-stranded DNA and requires divalent cations (Mg²⁺ or Ca²⁺) for full catalytic activity.

Biologically, DNase I plays a critical role in preventing aberrant immune activation triggered by cell-free or extracellular DNA. A central pathological substrate of DNase I is the neutrophil extracellular trap (NET) — web-like chromatin structures decorated with cytotoxic granular proteins, including neutrophil elastase, that are released by activated neutrophils in a process termed NETosis. When NET clearance is insufficient, accumulated DNA scaffolds drive sterile inflammation, immunothrombosis, and tissue injury across a spectrum of diseases ranging from systemic lupus erythematosus to acute lung injury (ALI) and cancer. The therapeutic administration of recombinant DNase I to enzymatically degrade these structures has therefore become a major focus in translational research.

Focus of Latest Publications

Recent publications spanning 2026 collectively position DNase I at the intersection of NET biology, cancer immunotherapy, inflammatory disease, and tissue engineering, reflecting broad and growing therapeutic interest.

NETs in oncology and immunotherapy. Several studies examined the role of DNase I in dismantling NET networks within the tumor microenvironment, where NETs are now recognized as drivers of immunosuppression, metastasis, and resistance to checkpoint inhibitor. A 2026 Biomaterials study described a neutrophil-surface-anchored DNase I platform (NE@LTT@DNase1) capable of dual-mode NET control: enzymatic degradation of pre-formed NETs via surface-anchored DNase I, and spatiotemporal suppression of new NETosis through an endogenous lysine-tryptophan-threonine (LTT) peptide that is activated in a reactive oxygen species (ROS)-dependent manner. This strategy was designed to convert the immunosuppressive properties of neutrophils into an anti-tumor force, with the goal of boosting neutrophil-mediated immunotherapy against solid tumors. Separately, a comprehensive review in the Journal of Hematology & Oncology catalogued the roles of NETs across the tumor microenvironment — encompassing interactions with macrophages, natural killer (NK) cells, and proinflammatory cytokines — and identified DNase I-mediated NET degradation as a rational complement to existing anti-tumor strategies, including those targeting PAD4 or neutrophil elastase. The review also noted the interplay between NETs and transforming growth factor-beta signaling in supporting metastatic niches.

NETs in cancer-associated anemia. A study published in Signal Transduction and Targeted Therapy uncovered a previously unrecognized mechanism by which tumor-derived DNA accumulates on the surface of reticulocytes, impairing their morphology and triggering erythrophagocytic clearance — thereby contributing to cancer-associated anemia, a phenomenon linked to proinflammatory cytokine activity and suppression of erythropoietin-driven erythropoiesis. Critically, treatment with DNase I enzymatically removed this surface-bound DNA, restored normal reticulocyte morphology, reduced erythrophagocytic clearance, and alleviated anemia in tumor-bearing mouse models, establishing extracellular DNA as a druggable mediator of this paraneoplastic complication.

Acute lung injury. A Journal of Controlled Release study introduced a nano-formulated DNase I system — produced by conjugating DNase I onto PEGylated bilirubin nanoparticles (BRn@DNase I) — to address the rapid plasma clearance that limits the therapeutic utility of free DNase I in ALI. The formulation was designed to efficiently scavenge cell-free DNA and resolve inflammation, with the bilirubin component additionally providing antioxidant activity to counteract the oxidative environment driving ALI pathology.

Gene therapy vectors and innate immune activation. Research published in Molecular Pharmaceutics demonstrated that insect-cell-produced AAV2 vectors activate a myeloid innate immune response featuring NETosis, and that degradation of extracellular DNA via DNase I significantly attenuated hepatic inflammatory signaling and enhanced vector transduction efficiency. This finding has direct implications for the safety and efficacy of gene therapy approaches, suggesting that DNase I co-treatment may be a valuable adjunct during viral vector administration.

Extracellular vesicle-mediated antigen presentation. A Cancer Cell study revealed that extracellular vesicles derived from activated T cells transfer DNA to antigen-presenting cells, enhancing antigen presentation and anti-tumor immunity through the programmed cell death 1 pathway. DNase I treatment was used experimentally to confirm the mechanistic role of this vesicle-associated DNA: removal of the DNA cargo abrogated antigen presentation protein (APP) upregulation, thereby abolishing T cell activation and tumor recruitment — providing a mechanistic tool as well as cautionary context for DNase I use in T cell-based therapeutic settings.

NET-targeted cancer nanomedicine with magnetic hyperthermia. A Biomaterials Advances study exploring superparamagnetic Fe₃O₄ nanoclusters for synergistic chemotherapy and NET degradation acknowledged DNase I's efficacy in NET clearance but highlighted its short plasma half-life as a core limitation, motivating the development of nanocarrier-based delivery platforms capable of sustaining enzymatic activity within the tumor microenvironment.

Tissue engineering. In a biomedical materials context, DNase I featured as an essential decellularization agent: a Biomedical Materials study on resource-efficient decellularization of human iliac arteries using a 3D-printed radial-flow bioreactor employed DNase I treatment following sodium dodecyl sulfate (SDS)-mediated cell lysis to degrade residual nuclear DNA, a standard step to reduce immunogenicity of engineered vascular grafts.

Key Publications

Jun Nano-sized DNase scavenges cell-free DNA for acute lung injury treatment. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 41865893): "we developed a nano-sized DNase system by conjugating DNase I onto PEGylated bilirubin (BR) nanoparticles (BRn@DNase I) for efficient cf-DNA scavenging and inflammation resolution in ALI."
Jun Insect-Cell-Produced AAV2 Vectors Activate Myeloid Innate Immune Response Featuring NETosis. (Molecular pharmaceutics, 2026, PMID 42157557): "Degradation of extracellular DNA via DNase I significantly attenuated hepatic inflammatory signaling and enhanced vector transduction."
May Resource-efficient decellularization of human iliac arteries using a 3D-printed radial-flow bioreactor: CFD-guided design and experimental validation. (Biomedical materials (Bristol, England), 2026, PMID 42102853): "Arteries were perfused radially for 8 d using a 1% w·v-1 sodium dodecyl sulfate solution, followed by deoxyribonuclease I treatment and phosphate-buffered saline washes."
May Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity. (Cancer cell, 2026, PMID 42066762): "DNase treatment removes most AT-EVDNA, abrogating APP upregulation and thus T cell activation and recruitment to tumors."
May Superparamagnetic Fe3O4 nanoclusters for cancer therapy and metastasis prevention via synergistic chemotherapy and NETs degradation. (Biomaterials advances, 2026, PMID 41529527): "Deoxyribonuclease I (DNase), while effective in NETs degradation, suffers from rapid plasma clearance, necessitating delivery vehicles to prolong its therapeutic activity."
Apr Tumor-derived DNA drives cancer-associated anemia by promoting reticulocyte clearance. (Signal transduction and targeted therapy, 2026, PMID 42031707): "Therapeutically, the enzymatic degradation of surface-bound DNA using Deoxyribonuclease I (DNase I) restores reticulocyte morphology, diminishes erythrophagocytic clearance, and alleviates anemia in tumor-bearing models."
Apr Neutrophil extracellular traps in the tumor microenvironment, metastasis, therapy, and beyond: advances, challenges, and perspectives. (Journal of hematology & oncology, 2026, PMID 41987275): "Based on these mechanisms, targeting NET formation (such as inhibiting PAD4 or NE) or degrading their structures (such as using DNase I) has emerged as a potential strategy to enhance the efficacy of existing therapies."
Apr Spatiotemporal controls of neutrophil extracellular traps boosts neutrophils immunotherapy efficiency against solid tumors. (Biomaterials, 2026, PMID 41587524): "Mechanistically, NE@LTT@DNase1 exerts dual therapeutic effects: (i) enzymatic degradation of pre-existing NETs via neutrophil surface-anchored DNase1 and (ii) spatiotemporal suppression of NETosis via endogenous lysine-trypotophan-threonine peptide (LTT) fragmentation in a reactive oxygen species-dependent manner."