Intraneural interfaces are stimulation/registration devices designed to couple the peripheral nervous system (PNS) with the environment. Over the last years, their use has increased in a wide range of applications, such as the control of a new generation of neural-interfaced prostheses. At present, the success of this technology is limited by an electrical impedance increase, due to an inflammatory response called foreign body reaction (FBR), which leads to the formation of a fibrotic tissue around the interface, eventually causing an inefficient transduction of the electrical signal. Based on recent developments in biomaterials and inflammatory/fibrotic pathologies, we explore and select the biological solutions that might be adopted in the neural interfaces FBR context: modifications of the interface surface, such as organic and synthetic coatings; the use of specific drugs or molecular biology tools to target the microenvironment around the interface; the development of bio-engineered-scaffold to reduce immune response and promote interface-tissue integration. By linking what we believe are the major crucial steps of the FBR process with related solutions, we point out the main issues that future research has to focus on: biocompatibility without losing signal conduction properties, good reproducible in vitro/in vivo models, drugs exhaustion and undesired side effects. The underlined pros and cons of proposed solutions show clearly the importance of a better understanding of all the molecular and cellular pathways involved and the need of a multi-target action based on a bio-engineered combination approach.