Restoring cellular calcium homeostasis to rescue ER stress by 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester-loaded lipid-mPLGA hybrid-nanoparticles for acute kidney injury therapy

Early pathogenesis of ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) is dominated by intracellular calcium overload, which induces oxidative stress, intracellular energy metabolism disorder, inflammatory activation, and a series of pathologic cascaded reactions that are closely intertwined with self-amplifying and interactive feedback loops, ultimately resulting in cell damage and kidney failure. Currently, most nanomedicines originate from the perspective of antioxidant stress, which can only quench existing reactive oxide species (ROS) but cannot prevent the continuous production of ROS, resulting in insufficient efficacy. As a safe and promising drug, BAPTA-AM is hydrolyzed into BAPTA by intracellular esterase upon entering cells, which can rapidly chelate with overloaded Ca2+, restoring intracellular calcium homeostasis, thus inhibiting ROS regeneration at the source. Here, we designed a KTP-targeting peptide-modified yolk-shell structure of liposome–poly(ethylene glycol)methyl ether-block-poly (l-lactide-co-glycolic) (mPLGA) hybrid nanoparticles (<100 nm), with the characteristics of high encapsulation rate, high colloid stability, facile modification, and prolonged blood circulation time. Once the BA/mPLGA@Lipo-KTP was targeted to the site of kidney injury, the cholesteryl hemisuccinate (CHEMS) in the phospholipid bilayer, as an acidic cholesterol ester, was protonated in the simulated inflammatory slightly acidic environment (pH 6.5), causing the liposomes to rupture and release the BA/mPLGA nanoparticles, which were then depolymerized by intracellular esterase. The BAPTA-AM was diffused and hydrolyzed to produce BAPTA, which can rapidly cut off the malignant loop of calcium overload/ROS generation at its source, blocking the endoplasmic reticulum (ER) apoptosis pathway (ATF4–CHOP–Bax/Bcl-2, Casp-12–Casp-3) and the inflammatory pathway (TNF-α–NF-κB–IL-6 axes), thus alleviating pathological changes in kidney tissue, thereby inhibiting the expression of renal tubular marker kidney injury molecule 1 (Kim-1) (reduced by 82.9%) and also exhibiting prominent anti-apoptotic capability (TUNEL-positive ratio decreased from 40.2% to 8.3%), significantly restoring renal function. Overall, this research holds huge potential in the treatment of I/R injury-related diseases.