Protein Immobilization Inspired Lysosomal Disruption for Efficient Nuclear Drug Delivery

The high metabolism and excessive growth of tumor cells result in the development of a tumor microenvironment (TME) and enhanced lysosomal activity within the cells, which can eliminate chemotherapeutics. Consequently, the design of nanocarriers that respond to TME and target tumor cell lysosomes represents an optimal strategy to enhance drug specificity and utilization efficiency. Herein, inspired by protein immobilization, a dual-responsive supramolecular nanomedicine FPA/DOX is developed for specifically targeting the TME and tumor cell lysosomes. Upon hypoxia and acidic response, FPA/DOX exposes benzaldehyde groups that engage with amino groups on lysosomal proteins by protein covalent immobilization reaction─an imidization condensation reaction, leading to protein denaturation and inactivation and inducing lysosomal membrane permeabilization (LMP). This LMP process not only triggers lysosomal-dependent cell death (LDCD) but also facilitates the rapid translocation of released DOX into the cell nucleus. <i>In vitro</i> experiments have demonstrated that the tumor cell toxicity of FPA/DOX is 4.2 times that of free DOX. Additionally, <i>in vivo</i> studies have verified the high biosafety of FPA/DOX, with a remarkable tumor inhibition rate of 95.27%. In summary, the lysosomal disruption inspired by protein immobilization has pioneered an approach for tumor treatment and holds great potential in biomedical applications.