Small intestinal submucosa (SIS) derived from porcine small intestine has been intensively studied for its capacity in repairing and regenerating wounded and dysfunctional tissues. However, SIS suffers from a large spectrum of heterogeneity in microarchitecture leading to inconsistent results. In this study, we introduced nanoparticles (NPs) to SIS with an intention of decreasing the heterogeneity and improving the consistency of this biomaterial. As determined by scanning electron microscopy and urea permeability, the optimum NP size was estimated to be between 200 nm and 500 nm using commercial monodisperse latex spheres. The concentration of NPs that is required to alter pore sizes of SIS as determined by urea permeability was estimated to be 1 mg/ml 260 nm poly(lactic-co-glycolic) acid (PLGA) NPs. The 1mg/ml PLGA NPs loaded in the SIS did not change the tensile properties of the unmodified SIS or even alter pH values in a cell culture environment. More importantly, PLGA NP modified SIS did not affect human mammary endothelial cells (HMEC-1) morphology or adhesion, but actually enhanced HEMC-1 cell growth.