Renal clearance is critical for nanodrug to avoid the long‐term body retention‐related side effects, while it is difficult to achieve efficient tumor accumulation and retention. The over‐developed lysosomes in cancer cells have become an emerging target for more precise and effective cancer therapy. Herein, a pH‐responsive reversible self‐assembled Cu2‐xSe‐BSA, which can be renal cleared under neutral or basic conditions, is developed for selectively targeted aggregation in cancer lysosomes with enhanced tumor accumulation and retention. Moreover, the aggregation of Cu2‐xSe‐BSA can enhance the photoacoustic imaging signal, photothermal therapy, and chemodynamic therapy capability. Cu2‐xSe‐BSA accumulated in lysosomes cannot only induce lysosomes swelling, but also generate reactive oxygen species in situ, causing lysosomal membrane permeabilization and finally lysosomal cell death. Notably, the assembled Cu2‐xSe‐BSA can dissociate to be renal clearable after the treatments are completed and left the acid tumor microenvironment, being of great significance both in scientific research and clinical trial.

Inflammatory bowel disease (IBD) is a chronic relapsing autoimmune disease with rising incidence worldwide. There is an increasing desire for non-invasive diagnostic tools to enable simple and sensitive IBD monitoring. Here, we report an orally administered nanosensor which will dissociate into ultrasmall platinum nanoclusters (PtNCs) in IBD-related inflammatory microenvironments. By exploiting the enzyme-mimicking activity of PtNCs and the precise bandpass filterability of kidney, the released-PtNCs can be detected in a scalable urinary readout, such as fluorescence and volumetric bar-chart chip (V-Chip), for point-of-care (POC) analysis. Our results demonstrate that the nanosensors exhibit significant signal differences between IBDmodel mice and healthy mice, which is more sensitive than clinical ELISA assay based on fecal calprotectin. Such a non-invasive diagnostic modality significantly assists in the personalized assessment of pharmacological and follow-up efficacy. We envision that this modular conception will promote the rapid diagnosis of diverse diseases by changing specific responsive components.

Type 2 diabetes (T2D) results from the cells’ insulin resistance, and to date, insulin therapy and diabetes medications targeting glycemic management have failed to reverse the increase in T2D prevalence. Restoring liver functions to improve hepatic insulin resistance by reducing oxidative stress is a potential strategy for T2D treatment. Herein, the liver-targeted biodegradable silica nanoshells embedded with platinum nanoparticles (Pt-SiO2) are designed as reactive oxygen species (ROS) nanoscavengers and functional hollow nanocarriers. Then, 2,4-dinitrophenol-methyl ether (DNPME, mitochondrial uncoupler) is loaded inside Pt-SiO2, followed by coating a lipid bilayer (D@Pt-SiO2@L) for long-term effective ROS removal (platinum nanoparticles scavenge overproduced ROS, while DNPME inhibits ROS production) in the liver tissue of T2D models. It is found that D@Pt-SiO2@L reverses elevated oxidative stress, insulin resistance, and impaired glucose consumption in vitro, and significantly improves hepatic steatosis and antioxidant capacity in diabetic mice models induced by a high-fat diet and streptozotocin. Moreover, intravenous administration of D@Pt-SiO2@L indicates therapeutic effects on hyperlipidemia, insulin resistance, hyperglycemia, and diabetic nephropathy, which provides a promising approach for T2D treatment by reversing hepatic insulin resistance through long-term ROS scavenging.