Supramolecular hacky sacks (SHS) are a distinct class of self-assembled colloidal particles derived from guanosine (G) derivatives, engineered to support a wide range of cellular and therapeutic functions. In this study, we examine how variations in G-derivative composition influence SHS cellular uptake, intracellular trafficking, and functional efficacy. Confocal microscopy and flow cytometry reveal that uptake is highly dependent on particle composition, indicating selective engagement with specific cellular mechanisms. We show that SHS particles are biocompatible carriers capable of delivering both small molecules and genetic material: they successfully encapsulate and release doxorubicin with enhanced cytotoxic effects, and enable plasmid transfection with sustained expression of fluorescent proteins. These findings position SHS particles as a highly adaptable and effective supramolecular platform for drug and gene delivery. Their intrinsic biodegradability, ease of preparation, and tunable bioactivity highlight their strong potential for advancing biomedical applications.