Drug carriers have been commonly used for drug control release, enhancing drug efficacy and/or minimizing side-effects. However, it is still difficult to get high loading efficiency when encapsulating super hydrophilic drugs with narrow therapeutic index, such as many neurotoxins. Increasing the carrier proportion can improve drug loading in a certain degree, while the burst released drug when the formulation enters the body may cause overdose side-effects. Moreover, high-dose carriers themselves may increase the metabolic burden of the body. Hence, new drug carriers and/or loading strategies are urgently needed to promote the applications of these drugs. This minireview will introduce drug loading strategies based on specific interactions (between drugs and carriers) and will discuss the challenges and perspectives of these strategies. This work is expected to provide alternative inspirations for the delivery of hydrophilic drugs.