Vitamin B12-Functionalized Nanogels for pH-, and Redox-Responsive Doxorubicin Delivery

Rapidly proliferating cancer cells display an elevated demand for vitamin B₁₂, rendering this bacterial-derived cofactor an attractive targeting motif for nanotherapeutic drug delivery. Herein, we report a concise two-step synthesis of a polymerizable 5′-modified vitamin B₁₂ -monomer that enables the covalent integration of B₁₂ into pH- and redox-responsive nanogels. The resulting nanogels efficiently encapsulate doxorubicin through electrostatic interactions between the cationic drug and the anionic nanogel network, while enabling stimuli-responsive drug release under tumor-relevant conditions. In vitro studies revealed that DOX@B₁₂-nanogels retain potent antiproliferative activity against HT-29 colorectal cancer cells (IC₅₀ = 0.878 ± 0.102 μM), while decreasing cytotoxicity toward healthy CCD 841 CoN cells by 34-fold relative to non-B₁₂-functionalized control nanogels. These findings establish covalently engineered vitamin B₁₂-nanogels as a promising platform for selective and stimuli-responsive anticancer drug delivery.