Translational nanorobotics breaking through biological membranes

In the dynamic realm of translational nanorobotics, the endeavor to develop nanorobots carrying therapeutics in rational in vivo applications necessitates a profound understanding of the biological landscape of the human body and its complexity. Within this landscape, biological membranes stand as critical barriers to the successful delivery of therapeutic cargo to the target site. Their crossing is not only a challenge for nanorobotics but also a pivotal criterion for the clinical success of therapeutic-carrying nanorobots. Nevertheless, despite their urgency, strategies for membrane crossing in translational nanorobotics remain relatively underrepresented in the scientific literature, signaling an opportunity for further research and innovation. This review focuses on nanorobots with various propulsion mechanisms from chemical and physical to hybrid mechanisms, and it identifies and describes four essential biological membranes that represent the barriers needed to be crossed in the therapeutic journey of nanorobots in in vivo applications. First is the entry point into the blood stream, which is the skin or mucosa or intravenous injection; next is the exit from the bloodstream across the endothelium to the target site; further is the entry to the cell through the plasma membrane and, finally, the escape from the lysosome, which otherwise destroys the cargo. The review also discusses design challenges inherent in translating nanorobot technologies to real-world applications and provides a critical overview of documented membrane crossings. The aim is to underscore the need for further interdisciplinary collaborations between chemists, materials scientists and chemical biologists in this vital domain of translational nanorobotics that has the potential to revolutionize the field of precision medicine.