Nanotechnology has revolutionized areas of biotechnology owing to its multidiversified applications, improved sensitivity, surface size, and cost. In the past years, some issues have arisen regarding the impact of nanomaterials on the environment and human health. In this regard, there is a growing interest in identifying natural and sustainable nanostructured biomaterials as an alternative to toxic petrochemical derived materials. The most commonly used materials in nanobiotechnology applications possess inherent limitations regarding biocompatibility, which leads to foreign-body response at the implantation site, causing a rejection of the implant. In parallel, the recovery of byproducts from other industries and their transformation into valuable resources have been key factors in the circular economy. Given that, there is urgency to move toward sustainable research and green nanotechnologies with an undeniable biocompatibility. Herein, we propose a design based on natural melanin nanoparticles (MNPs) obtained from the ink sacs of Sepia off icinalis, a waste product from the food industry, grafted with silane (MNPs GPTMS) for biomedical applications. The design, characterization of both physical and chemical properties, and biological properties of the MNPs GPTMS are reported. The silane, (3-glycidyloxypropyl)trimethoxysilane, allows facile functionalization of different bioreceptors onto the surface of MNPs GPTMS, herein demonstrated with antibodies and an enzyme. Cellular viability studies confirmed the cytocompatibility of MNPs GPTMS and hemocompatibility of 50 μg/mL. The engineered MNPs GPTMS provide a powerful, sustainable, and biocompatible biomaterial-based tool for specific bioreceptor targeting molecules that can be used in diverse biomedical field applications such as nanobiosensing.