Harvesting mechanical energy from biological systems possesses great potential for in-vivo powering implantable electronic devices. Nanogenerator (NG) is a promising technology for harvesting biomechanical energy either in vivo or ex vivo. In this talk, I present a development of flexible piezoelectric nanogenerator (NG) based on mesoporous poly(vinylidene fluoride) (PVDF) films. Monolithic mesoporous PVDF was fabricated by a template-free sol-gel-based approach at room temperature. By filling the pores of PVDF network with poly(dimethylsiloxane) (PDMS) elastomer, the composite’s modulus was effectively tuned over a wide range down to the same level of biological systems. A close match of the modulus between NG and the surrounding biological component is critical to achieve practical integration. Upon deformation, the composite NG exhibited appreciable piezoelectric output that was comparable to or higher than other PVDF-based NGs. An artificial artery system was fabricated using PDMS with the composite NG integrated inside. Effective energy harvesting from simulated blood pressure fluctuation was successfully demonstrated. The simple and effective approach for fabricating mesoporous PVDF with tunable mechanical properties provided a promising route toward the development of self-powered implantable devices. In vivo biomechanical energy harvesting was further demonstrated. The PVDF NG was encapsulated by polydimethylsiloxane (PDMS) and embedded into rodents. No toxicity or incompatibility sign was found in the host after carrying the packaged NG for 6 months. Moreover, the electric output of this NG was extremely stable and exhibited no deterioration during the entire implantation period. The outstanding efficiency, magnificent durability and exceptional biocompatibility promise this mesoporous PVDF-based NG in accomplishing self-powered bioelectronics with potentially lifespan operation period.