Nanomedicine has emerged as a promising mean to improve theranostic efficacy and reduce side effects. Currently, only very small percentage of injected dose reaches the solid tumors after intravenous administration due to the systemic biological barriers, including blood circulation, reticuloendothelial system capture, vasculature extravasation, tissue accumulation, deep penetration, cellular internalization, lysosome escape, intracellular efflux, and cell nuclear targeting. To optimize clinical translation and exploitation of nanomedicine, we here propose three safe and effective strategies to systematically overcome all barriers by the novel design of smart and bioinspired systems for highly efficient theranostics of various diseases, such as cancers, neurodegenerations, myocardial infarctions, inflammations, and infections. (1) Surface charge conversion, (2) size transformation, (3) bioinspired systems display unprecedented potential to achieve higher requirement of precise and personalized medicine. Alone or specially together, these strategies can address different barriers with intrinsically conflicting and promote the development of successful disease theranostics, that is impossible for almost of conventional delivery systems. Moreover, the challenges and perspectives of next-generation smart nanomedicine are featured for accurate theranostics and clinical practice in various diseases.