UC San Diego

Toxin threats are everywhere and underlie various diseases. Biological neutralization represents a strategy of deploying therapeutic agents to bind with toxin threats and neutralize their bioactivity. Despite their therapeutic potential, traditional neutralization platforms rely on targeting the molecular structure of individual toxic agents. This approach has been thwarted by the enormous structural diversity of toxic agents and yields narrow-spectrum neutralization with limited therapeutic efficacy. Recently, a novel class of biomimetic nanomedicine, known as “cellular nanosponges”, has emerged as a compelling neutralization platform. Composed of synthetic nanoparticle cores cloaked with natural cell membranes, cellular nanosponges mimic the host cells and can act as cell decoys to intercept and neutralize toxic agents. This neutralization strategy shifts the focus away from the distinct structures of toxic agents to their shared interactions with the host cells, thereby overcoming their structural diversity and enabling broad-spectrum neutralization. The first chapter of this dissertation reviews the recent progress in using cellular nanosponges for neutralization against bacterial toxins, chemical toxicants, inflammatory cytokines, pathological antibodies, and viruses. Despite their broad-spectrum neutralization capabilities, these nanosponges typically possess an inert core and rely solely on toxin binding with the membrane for neutralization. The second chapter presents a novel cellular nanosponge design featuring a functional core loaded with toxin-binding proteins. This design enables concurrent toxin binding by the membrane and core, leading to enhanced neutralization. Besides toxin-binding proteins, cellular nanosponges can encapsulate toxin-degrading enzymes to attain continuous toxin degradation and boost neutralization capacity. Such continuous toxin degradation can be accelerated by increasing the membrane permeability of cellular nanosponges. The third chapter presents membrane cholesterol depletion as a facile and versatile approach to enhance the membrane permeability of cellular nanosponges and accelerate toxin neutralization. Overall, this dissertation provides a framework for the rational design of protein-loaded cellular nanosponges for biological neutralization. This work is expected to inspire more innovations in the design of cellular nanosponges to address unsolved medical problems.