The tragic deaths of three patients in a recent AAV-based X-linked myotubular myopathy clinical trial highlight once again the pressing need for safe and reliable gene delivery vectors. Non-viral minimized DNA vectors offer one possible way to meet this need. Recent pre-clinical results with minimized DNA vectors have yielded promising outcomes in cancer therapy, stem cell therapy, stem cell reprograming, and other uses. Broad clinical use of these vectors, however, remains to be realized. Further advances in vector design and production are ongoing. An intriguing and promising potential development results from manipulation of the specific shape of non-viral minimized DNA vectors. By improving cellular uptake and biodistribution specificity, this approach could impact gene therapy, DNA nanotechnology, and personalized medicine.