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.