Methods of the early detection of diseases are based on recognition of the smallest change in the levels of a disease-specific biomarker in body fluids. Among them, monitoring protein concentrations is crucial because most diseases are caused by dysregulated protein levels, rather than DNA or RNA levels. Recent studies have indicated that the proteins in the aqueous humor can be used as biomarkers to predict brain diseases. Therefore, mounting an insertion type sensor on the intraocular lens is a compelling candidate platform for monitoring potential brain disease patients. In particular, molecular reactive sensors that use affinity binding, such as molecularly imprinted hydrogels, allow simple label-free detection, as well as high bio-applicability and biocompatibility. Herein, we describe the fabrication of an optical sensor using a silica nanoparticle conjugated bioresponsive hydrogel to analyze protein biomarkers by measuring light interference in smartphone images. Conformational changes in biotin-conjugated hydrogels were observed through the presence of avidin, as a substitution for a novel biomarker, in interconnecting hydrogel networks. Uniformly arrayed nanoparticles interfered with light differently when the distance between the silica nanoparticles was varied according to target moiety binding. A blue-shift of the reflected light was evident in avidin solutions of up to 100 nM and was induced by shrinkage of the hydrogel. The results indicate that our well-defined, label-free bioresponsive hydrogel demonstrated strong potential to be widely applied as a bioresponsive light interfering hydrogel sensor.