Nano carrier targeted drug delivery system has been widely concerned by many countries. Although papers published in this field have increased exponentially, no drug has come into the market successfully. Based on physicochemical and biological principles and through diffusion coefficient determination of nano carriers in different materials and particle sizes, this paper studies the different diffusion capacity of molecules and nanoparticles in aqueous media, as well as in vivo targeting process of the nanoparticles. After fundamental analysis of various theoretical misunderstanding for nano carriers targeted drug delivery system, we reveal that active targeting nanoparticles could not improve tumor targeting efficiency as their original designations. Then we draw a conclusion that EPR effect is only applicable for drug molecules and nano carriers with sufficient diffusion capacity, and propose new strategies for more feasible nano carriers targeted delivery, including environment-specific responded targeting drug release, improving the nano carrier diffusion capacity, using macrophage phagocytosis capturing NPs to achieve the target drug delivery, and step-by-step targeting strategy. nano carrier, active targeting, high efficient target, diffusion coefficient, EPR effect