Drug self-delivery systems: A comprehensive review on small molecule nanodrugs

Drug self-delivery systems are nanostructures composed of a drug as the main structural unit, having the ability of intracellular trafficking with no additional carrier. In these systems, the drug itself undertakes the functional and structural roles; thereby, the ancillary role of excipients and carrier-related limitations are circumvented and therapeutic effect is achieved at a much lower dose. Such advantages -which are mainly but not exclusively beneficial in cancer treatment- have recently led to an upsurge of research on these systems. Subsequently, various terminologies were utilized to describe them, referring to the same concept with different words. However, not all the systems developed based on the self-delivery approach are introduced using one of these keywords. Using a scoping strategy, this review aims to encompass the systems that have been developed as yet -inspired by the concept of self-delivery- and classify them in a coherent taxonomy. Two main groups are introduced based on the type of building blocks: small molecule-based nanomedicines and self-assembling hybrid prodrugs. Due to the diversity, covering the whole gamut of topics is beyond the scope of a single article, and, inevitably, the latter is just briefly introduced here, whereas the features of the former group are meticulously presented. Depending on whether the drug is merely a carrier for itself or carries a second drug as cargo, two classes of small molecule-based nanomedicines are defined (i.e., pure nanodrugs and carrier-mimicking systems, respectively), each having sub-branches. After introducing each branch and giving some examples, possible strategies for designing each particular system are visually displayed. The resultant mind map can create a macro view of the taken path and its prospects, give a profound insight into opportunities, spark new ideas, and facilitate overcoming obstacles. Taken together, one can foresee a brilliant future for self-delivery systems as a pioneering candidate for the next generation of drug delivery systems.