Exploitation of cholesterol-dependent cytolysins for targeted biosensing and therapeutic systems

Cholesterol-dependent cytolysins (CDCs) represent a unique and structurally conserved family of pore-forming toxins secreted by Gram-positive bacterial pathogens. These exotoxins significantly contribute to the virulence and pathogenicity of many CDC-expressing organisms. CDCs selectively recognize and bind cholesterol-rich membranes in host cells and undergo subsequent conformational changes leading to pore formation. Beyond their role as virulence factors, their unique membrane-targeting and pore-forming mechanisms have enabled promising avenues in precision biosensing and targeted therapeutic delivery. Recent advances in nanotechnology and biotechnology have enabled diverse and pivotal biomedical applications of CDCs, which encompass their exploitation as potential bacterial vaccine candidates, ligands for targeted drug delivery, biosensors for pathogen detection, and CDC-responsive nanocarriers for targeted therapeutic delivery. This review explores these emerging roles while highlighting critical factors for the design and evaluation of CDC-responsive platforms, as well as strategies for characterizing their interactions with biological systems. While several preclinical models have demonstrated promising in vitro and in vivo data, the clinical translation of CDC-associated therapies remains hindered by challenges which affect their widespread biomedical application. Understanding the biological mechanisms and molecular interactions of CDCs, along with the effective optimization of the physicochemical properties of CDC-targeted nanomaterials, holds great prospect in overcoming these challenges. Future research focusing on enhanced understanding of CDC physiological interactions and developing innovative CDC-responsive nanoplatforms for targeted delivery offers valuable prospects in advancing this field and may ultimately enable the successful clinical translation of CDC-based therapies. Despite current challenges in ongoing research, the strategic exploitation of CDCs holds significant potential in the advancement of targeted biosensing and therapeutic innovations.