Biological delivery remains a major challenge in biotechnology, partly because it is often not enough to overcome a single delivery barrier. It is highly desirable, yet rarely available, to design...

Most neurological diseases have no cure today; innovations in neurotechnology are in urgent need. Nanomaterial-based remote neurostimulation with physical fields (NNSPs) is an emerging class of neurotechnologies that has generated tremendous interest in recent years. This perspective focuses on the clinical translation of this new class of neurotechnologies, an issue that so far has not received enough attention. We outline the major barriers in their clinical translation. We highlight our recent efforts to tackle these translational barriers, with a focus on the biological delivery problem. In particular, for the first time, we have shown that it is feasible to use noninvasive brain delivery to generate significant physiological responses in living animals by NNSP. However, much more work is needed to overcome the translational barriers.

The so-called “hard-to-transfect cells” are well-known to present great challenges to intracellular delivery, but detailed understandings of the delivery behaviors are lacking. Recently, we discovered that vesicle trapping is a likely bottleneck of delivery into a type of hard-to-transfect cells, namely, bone-marrow-derived mesenchymal stem cells (BMSCs). Driven by this insight, herein, we screened various vesicle trapping–reducing methods on BMSCs. Most of these methods failed in BMSCs, although they worked well in HeLa cells. In stark contrast, coating nanoparticles with a specific form of poly(disulfide) (called PDS1) nearly completely circumvented vesicle trapping in BMSCs, by direct cell membrane penetration mediated by thiol–disulfide exchange. Further, in BMSCs, PDS1-coated nanoparticles dramatically enhanced the transfection efficiency of plasmids of fluorescent proteins and substantially improved osteoblastic differentiation. In addition, mechanistic studies suggested that higher cholesterol content in plasma membranes of BMSCs might be a molecular-level reason for the greater difficulty of vesicle escape in BMSCs.

Microscopic particles (nano- and micro-particles) have shown great potential as biological delivery carriers, with notable success stories such as DOXIL and COVID-19 vaccines. Translation of these advanced drug delivery systems...