Erythrocyte-derived particles activated by near-infrared (NIR) light present a platform for various photo-theranostic applications. We have engineered such a platform with indocyanine green (ICG) as the NIR-activated agent. A particular feature of these particles is that their diameters can be tuned from micro- to nano-scale, providing a potential capability for broad clinical utility ranging from vascular to cancer-related applications. An important issue related to clinical translation of these particles is their immunogenic effects. Herein, we have evaluated the early-induced innate immune response of these particles in healthy Swiss Webster (SW) mice following tail vein injection by measurements of specific cytokines in blood serum, liver, and spleen following euthanasia. In particular, we have investigated the effects of particles size and relative dose, time-dependent cytokines response for up to 6 hours post-injection, functionalization of the nano-sized particles with folate or Herceptin?, and dual injections of the particles one week apart. Mean concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1 in response to injection of micro-sized particles at the investigated relative doses were significantly lower than the corresponding mean concentrations induced by lipopolysaccharide (positive control) at 2 hours. All investigated doses of the nano-sized particles induced significantly higher concentrations of MCP-1 in liver and spleen as compared to phosphate buffer saline (PBS) (negative control) at 2 hours. In response to micro- and nano-sized particles at the highest investigated dose, there were significantly higher levels of TNF-α in blood serum at 2 and 6 hours post-injection as compared to the levels associated with PBS treatment at these times. Whereas the mean concentration of TNF-α in liver significantly increased when comparing the levels 2 and 6 hours post-injection in response to the injection of the micro-sized particles, it was significantly reduced when comparing 2 and 6 hours following the injection of the nano-sized particles. In general, functionalization of the nano-sized particles was associated with a reduction of IL-6 and MCP-1 in blood serum, liver, and spleen, and TNF-α in blood serum. With the exception of IL-10 in the spleen in response to nano-sized particles, the second injection of micro- or nano-sized particles did not lead to significantly higher concentrations of other cytokines at the investigated dose as compared to a single injection.