Vesicle-based drug delivery systems provide a versatile platform that encapsulates hydrophilic and hydrophobic drugs in distinct compartments, overcoming limitations of conventional formulations in handling diverse physicochemical properties. Hydrophilic drugs suffer from degradation and poor membrane permeability, while hydrophobic drugs show low solubility and limited bioavailability; both face inefficient membrane crossing. By localizing hydrophilic molecules in the aqueous core and hydrophobic drugs in the lipid bilayer, vesicular carriers enable compartment-specific loading and distinct release under redox conditions. In this study, structurally identical drug pairs, including doxorubicin/doxorubicin hydrochloride and clindamycin/clindamycin phosphate, were co-encapsulated to investigate release dynamics and biological effects. Hydrophobic drugs in the bilayer showed rapid burst release followed by sustained release from hydrophobic interactions, whereas hydrophilic drugs in the core displayed slower but accelerated release as diselenide linkages were cleaved. These compartment-dependent differences generated distinct intracellular trafficking and pharmacological profiles, indicating that spatial localization within vesicles dictates therapeutic onset and efficacy. Overall, these findings highlight vesicle-based dual loading as a strategy for precision delivery through tailored spatiotemporal release, enabling organelle-targeted and adaptive cancer therapy.