Engineering stable multi-component pH responsive nanomedicine for enhanced photothermal/photodynamic therapy

Integrating multiple modalities of cancer therapies for synergistic and enhanced therapeutic efficacy remains challenging. Herein, flash nanoprecipitation (FNP), a kinetically driven process, was employed to expedite the coordination reaction time required for nano-encapsulate components with completely opposite physiochemical properties including sorafenib (SRF), hemoglobin (Hb), chlorin e6 (Ce6), and indocyanine green (ICG) into a multi-component HSCI nanomedicine. Hydrophilic components Hb and ICG interact to form hydrophobic ICG-Hb complexes under electrostatic and hydrophobic interactions. This process facilitates the characteristic time of nucleation (τ_nucleation) to match the characteristic mixing time (τ_mix) of the FNP process, resulting in the formulation of kinetically stable nanomedicine, overcoming the long equilibrium times and instability issues associated with thermodynamic assembly. Importantly, pH-responsive structure is also easily but effectively integrated in nanomedicine during this kinetically driven formulation to manipulate its structures. In the acidic tumor microenvironment (TME), the pH-stimulated morphology transformation of HSCI nanomedicine boosts its reactive oxygen species (ROS) generation efficiency and photothermal efficacy, endowing it with better antitumor suppression. In vitro and in vivo experiments reveal that the HSCI nanomedicine offers a synergistic therapeutic effect and stronger tumor suppression compared with single therapies. These results open a new window for developing strategies for multimodal combinatory cancer therapies.