Dysfunction of the lysosome and autophagy–lysosome pathway is closely associated with various diseases, such as neurodegenerative diseases, non-alcoholic fatty liver disease (NAFLD), etc. Additionally, chloroquine is a clinically widely used drug for treating malaria and autoimmune diseases, but long-term or high-dose administration may lead to significant toxic side effects. Attapulgite (ATT), a natural nanomaterial with excellent adsorption capacity and biocompatibility, herein demonstrated a novel biological function in regulating the lysosomal and autophagy–lysosome pathway. ATT could be effectively internalized into lysosome-related acidic compartments. Further study revealed that ATT could restore lysosomal pH, activate cathepsin D, alleviate autophagy blockage in chloroquine-treated cells, and reduce chloroquine-elicited cell death. In a cell model related to Huntington’s disease, treatment with ATT reinforced the degradation of the mutant huntingtin proteins by increasing cathepsin D maturation and autophagy flux. ATT could also promote lipid droplet clearance in hepatocytes with palmitic acid-induced steatosis, reduce hepatic lipid accumulation, and improve fasting blood glucose in high-fat-diet-induced NAFLD mice. These findings establish ATT as a lysosomal modulator, providing a foundation for its therapeutic potential in mitigating the adverse effects associated with long-term chloroquine use, especially improving neurodegenerative and metabolic disorders.

Mutations in the p53 gene are frequently observed in various cancers, prompting the initiation of efforts to restore p53 function as a therapeutic approach several decades ago. Nevertheless, only a limited number of drug development initiatives have progressed to late-stage clinical trials, and to date, no p53-targeted therapies have received approval in the USA or Europe. This situation can be attributed primarily to the characteristics of p53 as a nuclear transcription factor, which lacks the conventional features associated with drug targets and has historically been considered “undruggable”. In recent years, however, several promising strategies have emerged, including the enhanced iterations of previous approaches and novel techniques aimed at targeting proteins that have traditionally been considered undruggable. There is a growing interest in small molecules that can restore the tumor-suppressive functions of mutant p53 proteins, and the development of drugs specifically designed for particular p53 mutation types is currently underway. Other approaches aim to deplete mutant p53 or exploit vulnerabilities associated with its expression. Additionally, genetic therapy strategy and approaches have rekindled interest. Advances in mutant p53 biology, compound mechanisms, treatment modalities, and nanotechnology have opened up new avenues for p53-based therapies. However, significant challenges remain in clinical development. This review reassesses the progress in targeting p53-mutant cancers, discusses the obstacles in translating these approaches into effective therapies, and highlights p53-based therapies via nanotechnology.