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The innate immune system is the first line of defense against microbial invasion and involves the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors on the surface of phagocytic cells. The immune system also responds to tissue damage, a process that is triggered by so-called danger- or damage-associated molecular patterns (DAMPs) or “alarmins”. How do physico-chemical properties e.g., size, shape, surface charge and solubility affect immune interactions of nanoparticles? Does the adsorption of biomolecules onto the surface of nanoparticles dictate subsequent immune responses? Do engineered nanoparticles per se act as “alarmins” or does the bio-corona on nanoparticles convey a new “identity” and allow innocuous nanoparticles to present NAMPs (nanoparticle-associated molecular patterns)? Finally, what are the parameters that determine particle clearance or biodegradation in a living system? Understanding nano-immuno-interactions is critical for the safe application of engineered nanoparticles in medicine.