Reactive oxygen species (ROS) are key pathological signals expressed in inflammatory diseases such as cancer, ischemic conditions and atherosclerosis. An ideal drug delivery system should not only be responsive to these signals but also should not elicit an unfavourable host response. This study presents an innovative platform for drug delivery where a natural/synthetic composite system composed of collagen type I and a synthesized polythioether, ensures a dual stimuli-responsive behaviour. Collagen type I is an extracellular matrix constituent protein, responsive to matrix metalloproteinases (MMP) cleavage per se. Polythioethers are stable synthetic polymers characterized by the presence of sulphur, which undergoes a ROS-responsive swelling switch. A polythioether was synthesised, functionalized and tested for cytotoxicity. Optimal conditions to fabricate a composite natural/synthetic hollow sphere construct were optimised by a template-based method. Collagen-polythioether hollow spheres were fabricated, revealing uniform size and ROS-triggered nanoporation features. Cellular metabolic activity of H9C2 cardiomyoblasts remained unaffected upon exposure to the spheres. Our natural/synthetic hollow microspheres exhibit the potential for use as a pathological stimuli-responsive reservoir system for applications in inflammatory diseases.