No abstract

The development of nanomedicine formulations to overcome the disadvantages of traditional chemotherapeutic drugs and integrate cooperative theranostic modes still remains challenging. Herein, we report the facile construction of a multifunctional theranostic nanoplatform based on doxorubicin (DOX)-loaded tannic acid (TA)–iron (Fe) networks (for short, TAF) coated with fibronectin (FN) for combination tumor chemo-/chemodynamic/immune therapy under the guidance of magnetic resonance (MR) imaging. We show that the DOX-TAF@FN nanocomplexes created through in situ coordination of TA and Fe­(III) and physical coating with FN have a mean particle size of 45.0 nm, are stable, and can release both DOX and Fe in a pH-dependent manner. Due to the coexistence of the TAF network and DOX, significant immunogenic cell death can be caused through enhanced ferroptosis of cancer cells via cooperative Fe-based chemodynamic therapy and DOX chemotherapy. Through further treatment with programmed cell death ligand 1 antibody for an immune checkpoint blockade, the tumor treatment efficacy and the associated immune response can be further enhanced. Meanwhile, with FN-mediated targeting, the DOX-TAF@FN platform can specifically target tumor cells with high expression of αvβ3 integrin. Finally, the TAF network also enables the DOX-TAF@FN to have an r 1 relaxivity of 6.1 mM–1 s–1 for T 1-weighted MR imaging of tumors. The developed DOX-TAF@FN nanocomplexes may represent an updated multifunctional nanosystem with simple compositions for cooperative MR imaging-guided targeted chemo-/chemodynamic/immune therapy of tumors.

Transition of acute kidney injury (AKI) to chronic kidney disease (CKD) represents an important cause of kidney failure. However, how AKI is transformed into CKD remains elusive. Following folic acid injury, mice developed AKI with ensuing CKD transition, featured by variable degrees of interstitial fibrosis and tubular cell atrophy and growth arrest. This lingering injury of renal tubules was associated with sustained oxidative stress that was concomitant with an impaired Nrf2 antioxidant defense, marked by mitigated Nrf2 nuclear accumulation and blunted induction of its target antioxidant enzymes, like heme oxygenase (HO)-1. Activation of the canonical Keap1/Nrf2 signaling, nevertheless, seems intact during CKD transition because Nrf2 in injured tubules remained activated and elevated in cytoplasm. Moreover, oxidative thiol modification and activation of Keap1, the cytoplasmic repressor of Nrf2, was barely associated with CKD transition. In contrast, glycogen synthase kinase (GSK)3β, a key modulator of the Keap1-independent Nrf2 regulation, was persistently overexpressed and hyperactive in injured tubules. Likewise, in patients who developed CKD following AKI due to diverse etiologies, like volume depletion and exposure to radiocontrast agents or aristolochic acid, sustained GSK3β overexpression was evident in renal tubules and coincided with oxidative damages, impaired Nrf2 nuclear accumulation and mitigated induction of antioxidant gene expression. Mechanistically, the Nrf2 response against oxidative insult was sabotaged in renal tubular cells expressing a constitutively active mutant of GSK3β, but reinforced by ectopic expression of dominant negative GSK3β in a Keap1-independent manner. In vivo in folic acid-injured mice, targeting GSK3β in renal tubules via conditional knockout or by weekly microdose lithium treatment reinstated Nrf2 antioxidant response in the kidney and hindered AKI to CKD transition. Ergo, our findings suggest that GSK3β-mediated Keap1-independent regulation of Nrf2 may serve as an actionable therapeutic target for modifying the long-term sequelae of AKI.