Spider silk has been in the focus of research mainly due to the superior mechanical characteristics of silk fibers. However, it has been previously shown that spider silk proteins can also adopt other morphologies such as submicroparticles. This study examines the applicability of such particles as drug carriers. Particle characterization revealed that particles made of the engineered spider silk protein eADF4(C16) are colloidally stable in solution. Here, it is shown that small molecules with positive net-charge can diffuse into the negatively charged spider silk protein matrix driven by electrostatic interactions. The loading efficiencies correlate with the distribution coefficient (logD) of small molecules of weak alkaline nature. Interestingly, constant release rates can be realized for a period of two weeks at physiological conditions in vitro, with accelerated release rates within acidic environments. Enzymatic degradation studies of eADF4(C16) particles indicated that the silk proteins degrade slowly and the particles decrease in size. Along with their all-aqueous and easy preparation, drug loaded eADF4(C16) particles provide a high potential for diverse applications in which controlled release from biodegradable carriers is desired.