Discovery of a Novel Nephroprotective Drug Leveraging a Customized Photoacoustic Imaging Nanoprobe

ABSTRACT Renal ischemia‐reperfusion injury (IRI), which is exacerbated when blood flow is restored to ischemic organs, frequently complicates cardiothoracic and renal surgeries and is a major contributor to acute kidney failure and post‐transplant graft damage. In this study, we developed a photoacoustic (PA) imaging nanoprobe (TB@MP NP) for the reversible detection of peroxynitrite and glutathione, providing a novel diagnostic approach for IRI. Moreover, it allowed for real‐time monitoring of IRI via noninvasive PA imaging with significantly higher detection sensitivity than conventional blood tests. Furthermore, this nanoprobe was used to establish a robust screening platform for identifying nephroprotective agents from a library of natural products. A critical outcome of this screening was the first reported discovery of squalene's therapeutic potential for IRI. Following oral administration, squalene effectively alleviated renal injury without causing adverse effects on other healthy tissues, including the heart, liver, spleen, lung, kidney, and intestine. Its therapeutic mechanism involved the simultaneous suppression of oxidative stress, inflammatory responses, and the protein kinase B/nuclear factor kappa B signaling pathway. Collectively, the newly developed PA imaging nanoprobe and the identified drug candidate constitute an integrated diagnostic and therapeutic strategy, with substantial potential for the early detection and effective intervention of IRI.