Upconverting Nanoparticle-Containing Erythrocyte-Sized Hemoglobin Microgels That Generate Heat, Oxygen and Reactive Oxygen Species for Suppressing Hypoxic Tumors

Inspired by erythrocytes that contain oxygen-carrying hemoglobin (Hb) and that exhibit photo-driven activity, we introduce homogenous-sized erythrocyte-like Hb microgel (mu Gel) systems (5-6 mu m) that can (i) emit heat, (ii) supply oxygen, and (iii) generate reactive oxygen species (ROS; O-1(2)) in response to near-infrared (NIR) laser irradiation. Hb mu Gels consist of Hb, bovine serum albumin (BSA), chlorin e6 (Ce6) and erbium@lutetium upconverting nanoparticles (UCNPs; similar to 35 nm) that effectively convert 808 nm NIR light to 660 nm visible light. These Hb mu Gels are capable of releasing oxygen to help generate sufficient reactive oxygen species (O-1(2)) from UCNPs/Ce6 under severely hypoxic condition upon NIR stimulation for efficient photodynamic activity. Moreover, the Hb mu Gels emit heat and increase surface temperature due to NIR light absorption by heme (iron protoporphyrin IX) and display photothermal activity. By changing the Hb/UCNP/Ce6 ratio and controlling the amount of NIR laser irradiation, it is possible to formulate bespoke Hb mu Gels with either photothermal or photodynamic activity or both in the context of combined therapeutic effect. These Hb mu Gels effectively suppress highly hypoxic 4T1 cell spheroid growth and xenograft mice tumors in vivo.