Precision Temperature Control of Volume Phase Transition in Biocompatible PEG-Based Nanogels for Triggered Drug...

Thermoresponsive nanogels (NGs) can reversibly alter their structure in response to temperature changes. This enables controlled drug release, targeted therapy, and improved treatment precision under physiological or externally applied thermal conditions. Despite these advantages, few studies have systematically tuned the volume phase transition temperature (VPTT) of oligo-(ethylene glycol) methacrylates (OEGMA)-based NGs across physiologically relevant temperatures while maintaining stability and biodegradability. In this work, NGs were synthesized using di-(ethylene glycol) methyl ether methacrylate (DEGMA), tri-(ethylene glycol) methyl ether methacrylate (TEGMA), and 2-methoxyethyl methacrylate (MOEMA) monomers, achieving finely tuned VPTT with a precision within 1 °C. The NGs exhibited diameters ranging from 200 to 350 nm and a negative ζ-potential. Upon reaching the VPTT, the NGs shrank to sizes below 100 nm while becoming monodisperse. Specifically, NG@TEGMA exhibited VPTT between 50-60 °C, NG@DEGMA between 30-45 °C, and NG@TEGMA_DEGMA between 64-66 °C, and NG@TEGMA_MOEMA with molar ratios of 40%, 30%, and 20% displayed VPTT of 37, 47, and 52 °C, respectively. NG@TEGMA NGs were further polymerized with a methacrylated docetaxel derivative, achieving an encapsulation efficiency of 93 ± 4%. These NGs released approximately 90% of the drug upon reaching the VPTT, while nonthermoresponsive controls only released about 20% of the drug. Furthermore, NG@TEGMA demonstrated negligible cytotoxicity and efficient cellular uptake. This study demonstrates a biocompatible and degradable platform of OEGMA-based thermoresponsive NGs for biomedical applications such as hyperthermia-driven drug delivery for cancer therapy with superior thermoresponsive behavior to previously reported OEGMAs-, NIPAM-, or VCL-based NGs.