Engineering Size-Controlled Erythrocyte-Derived Particles for NIR-Responsive Theranostic Applications in Oropharyngeal Carcinoma.

Erythrocyte membranes, also known as ghosts, can be utilized as drug carriers or camouflaging membranes for drug delivery systems due to their "self-to-biological system" nature. However, size modulation of erythrocyte ghosts may influence their drug loading capabilities, cellular uptake, and performance as drug carriers. Herein, we have prepared micron-sized Near infrared Erythrocyte Particles (µNiEP) and nanosized variants (NiEP400, NiEP100) erythrocyte-derived particles using whole human blood and encapsulated with a near infrared fluorophore, indocyanine green (ICG). Size modulation of ICG-loaded erythrocyte ghosts is achieved through hypotonic lysis and regulated extrusion. Physico-chemical characterization confirms preservation of specific membrane proteins, including CD47, indicating immune evasion abilities across all three formulations. Size-dependent cellular uptake studies in Detroit-562 oropharyngeal cancer cells reveal that NiEP100 demonstrates superior penetration and intracellular distribution. NIR laser-mediated photothermal studies unveil NiEP100 showing uptake-correlated cytotoxicity enhancement (∼1.8-fold). NiEP400 shows limited therapeutic benefit (∼0.9-fold) with moderate uptake. All displayed macrophage evasion through inherent biomimetic properties. These findings establish a vital size-performance relationship for erythrocyte-based particles. This study provides a foundation for developing optimized, patient-tailored cancer therapeutic platforms with enhanced therapeutic indices and clinical translation potential.