Temperature‐Buffer Interplay Governs the Formation, Stability, and Degradation of POEGMA Nanogels

Recent advancements in soft nanomaterials have positioned nanogels at the interface of polymer chemistry and biomedicine, as they combine the physicochemical features of nanoparticles with the three‐dimensional, water‐swollen architecture of hydrogels. This study explored the formation and properties of degradable nanogels from thermoresponsive poly[oligo(ethylene glycol) methacrylates] (POEGMA), indicating their potential as drug carriers. The research underscored the importance of biologically relevant conditions, as nanogel formation and degradation were more challenging in buffer solutions (citrate and PBS) than in water. During synthesis through dual thermal and chemical crosslinking, aggregation occurred when the milieu temperature exceeded the polymers’ cloud point temperature ( T CP ), revealing a medium and temperature‐dependent processing regime. Obtaining nanogels of suitable size required an appropriate temperature gap between the polymer's T CP and the temperature of the biological medium. Nanogel degradation in citrate buffer and PBS was followed by dynamic light scattering and cryogenic transmission electron microscopy, and encapsulation and release of doxorubicin hydrochloride were demonstrated. Our findings highlight that translation from simplified aqueous solutions to biological media fundamentally alters nanogel formation, stability and degradation pathways. By identifying temperature‐medium interdependencies as a key design parameter, this work provides chemically grounded guidelines for the rational development of nanogels made of thermoresponsive polymers intended for future applications.