Abstract: OBJECTIVE We developped xanthotoxin loaded PLGA nanospheres for topical formulation and to investigate its influences on PUVA photoreaction toxicity with the final goal of ameliorating the efficacy of PUVA therapy. METHODS Xanthotoxin loaded PLGA nanospheres were prepared by interfacial polymer deposition following solvent displacement and the formulation was optimized and we investigated its in vitro released profiles across artificial dialysis membrane, meanwhile its efficacy of photo-reaction using psoralen-DNA interaction model was determined. RESULTS The nanospheres optimized had a mean diameter (109 nm), a narrow size distribution (polydispersity index<0.1), and a negative surface charge (zeta potential <-20 mV). Its encapsulation efficiency was about 65.8%.The release of xanthotoxin from nanospheres was significantly faster than from the correspondent Meladinine solution. Xanthotoxin incorporated in the nanospheres can decrease the velocity of photoreaction with DNA. CONCLUSION Xanthotoxin loaded PLGA nanospheres for topical formulation could constitute a promising approach for controlling the xanthotoxin release in order to maintain its therapeutic activity with less side effects.