Construction of triple-responsive nanogel embedded with upconversion nanoparticles via microemulsion polymerization for near-infrared-controlled drug delivery

It was generally accepted that ultra-violet (UV) light was prone to suffer from shallow tissue penetration and potential cell phototoxicity, limiting its further application in biomedical field. To overcome this shortcoming, a novel triple-responsive nanogel embedded with upconversion nanoparticles (UCNPs), β-NaYF₄:Yb,Tm, was constructed by emulsion polymerization of photo-responsive SPMA, temperature-sensitive N-isopropylacrylamide (NIPAM), and pH-responsive methacrylic acid (MAA). A series of characterizations were used to prove successful synthesis of the composite nanogel. The system exhibited reversible volume change in response to pH, temperature, and near-infrared (NIR) light, enabled by UCNPs-mediated photoactivation. With doxorubicin (DOX) as a model molecule, drug loading efficiency of composite nanogel could attain relatively high value of 53.06 ± 1.58 %. High release efficiency of 90.53 % could be achieved under UV light, 73.64 % under NIR light, and 82.17 % at pH = 3 & 30 °C, with minimal release efficiency (<6%) under normal physiological condition (pH = 7, 36 °C), confirming controllable releasing behaviors of the nanogel. Also, the drug releasing process could be well fitted with Weibull model. Cytocompatibility assays confirmed the nanogels’ safety (87.6 % viability at 500  μg/mL), while DOX-loaded nanogels showed significant cytotoxicity toward A549 cells (≤10 % viability, p ≤ 0.001). This study highlighted the potential of UCNPs-doped nanogels for smart, on-demand, and minimally invasive cancer therapy.