In situ implantable DNA hydrogel for diagnosis and therapy of postoperative rehemorrhage following intracerebral hemorrhage surgery.

Postoperative rehemorrhage following intracerebral hemorrhage surgery is intricately associated with a high mortality rate, yet there is now no effective clinical treatment. In this study, we developed a hemoglobin (Hb)-responsive in situ implantable DNA hydrogel comprising Hb aptamers cross-linked with two complementary chains and encapsulating deferoxamine mesylate (DFO). Functionally, the hydrogel generates signals upon postoperative rehemorrhage by capturing Hb, demonstrating a distinctive "self-diagnosis" capability. In addition, the ongoing capture of Hb mediates the gradual disintegration of the hydrogel, enabling the on-demand release of DFO without compromising physiological iron-dependent functions. This process achieves self-treatment by inhibiting the ferroptosis of neurocytes. In a collagenase and autologous blood injection model-induced mimic postoperative rehemorrhage model, the hydrogel exhibited a 5.58-fold increase in iron absorption efficiency, reducing hematoma size significantly (from 8.674 to 4.768 cubic millimeters). This innovative Hb-responsive DNA hydrogel not only offers a therapeutic intervention for postoperative rehemorrhage but also provides self-diagnosis feedback, holding notable promise for enhancing clinical outcomes.

Prodrug nanoparticles potentiate tumor chemo-immunometabolic therapy by disturbing oxidative stress.

Constant oxidative stress and lactate accumulation are two main causes of tumor immunosuppression, their concurrent reduction plays a dominant role in effective antitumor immunity, but remains challenging. Herein, reactive oxygen species (ROS) responsive prodrug nanoparticles (designed as DHCRJ) are constructed for metabolic amplified chemo-immunotherapy against triple-negative breast cancer (TNBC) by modulating oxidative state and hyperglycolysis. Specifically, DHCRJ is prepared by the self-assembly of DOX prodrug-tethered ROS consuming bond-bridged copolymers with the loading of bromodomain-containing protein 4 inhibitor (BRD4i) JQ1. Interestingly, the nanoparticle polymer network could reduce ROS to relieve tumor hypoxia and realize the dense-to-loose structure inversion arising from ROS-triggered network collapse, which favors JQ1 release and hyaluronidase (Hyal)-activatable DOX prodrugs generation. More importantly, disruption of oxidative stress decreases glucose uptake and assists JQ1 to down-regulate oncogene c-Myc driven tumor glycolysis for blocking the source of lactate and reshaping immunosuppressive tumor microenvironment (ITME). Meanwhile, benefiting from the synergistic effect of DOX prodrugs and JQ1, DHCRJ is able to facilitate tumor immunogenicity and potentiate systemic immune responses through antigen processing and presentation pathway. In this manner, DHCRJ significantly suppresses tumor growth and metastasis with prolonged survival. Collectively, this study represents a proof of concept antioxidant-enhanced chemo-immunometabolic therapy strategy using ROS-reducing nanoparticles for efficient synergistic therapeutic modality of TNBC.