Advances in IR-780-derived theranostics: A comparative analysis of free and nanoencapsulated forms

IR-780 is a lipophilic heptamethine cyanine dye that exhibits strong absorption and fluorescence emission in the near-infrared (NIR) region (700-900 nm). Similar to other cyanine dyes, IR-780 is emerging as a promising fluorophore for fluorescence-guided surgery (FGS). In addition, due to its high molar extinction coefficient, IR-780 can generate reactive oxygen species (ROS), enable efficient conversion of light into heat, and impart additional phototherapeutic capabilities. Consequently, IR-780 represents a promising "all-in-one" single molecule for FGS and phototherapy applications. However, its use is limited by poor aqueous solubility, low photostability, and rapid clearance, which restrict its bioavailability and reproducibility in clinical contexts. Recent strategies to address these drawbacks include both structural modification of IR-780 and nanoparticle (NP)-based delivery approaches. NP encapsulation using lipid-based, polymeric, inorganic, or biomimetic carriers has proven effective in enhancing aqueous solubility and photostability, reducing off-target cytotoxicity, and thereby improving imaging and therapeutic precision. This review systematically compares free and NP-encapsulated IR-780 and its derivatives, highlighting key differences in photophysical and physicochemical properties, in vitro and in vivo outcomes, and NP design considerations. Overall, while the free dye allows straightforward administration, NP formulations provide superior photophysical performance, improved biodistribution control and greater tumor retention. However, they remain limited by challenges in large-scale translation and regulatory approval.