To date, several targeted therapies have been developed for their clinical use, exhibiting increased cancer cell specificity. PROteolysis TArgeting Chimeras (PROTACs) are small molecules designed to induce the degradation of target proteins via proteasome after their ubiquitination. These molecules represent the most recent strategy of targeting specific proteins for post-translational degradation rather than simply inhibiting them. Despite the promising efficacy of PROTAC-based targeted therapies, significant drawbacks remain regarding their clinical translation. Advances in drug delivery systems (DDS) and nanotechnology offer innovative strategies to overcome these limitations and optimize the therapeutic index of PROTACs, through the use of several nanocarriers including lipid-based nanoparticles, polymeric nanoparticles or metallic nanoparticles, among others. In light of the exponential growth of preclinical studies, this review summarizes key achievements in the development of PROTACs and nanoPROTACs, highlighting how DDS can improve their mechanism of action and facilitate future clinical applications. Furthermore, recent research has focused on addressing critical challenges related to the permeability, bioavailability, and toxicity of these molecules, paving the way for more effective and safer therapeutic options. Continued interdisciplinary efforts integrating medicinal chemistry, nanotechnology and oncology are essential to fully exploit the potential of PROTACs.