The key challenge for the broad application of implantable biofuel cells (BFCs) is to achieve inorganicorganic composite biocompatibility while improving the activity and selectivity of the catalysts.W eh ave fabricated nanoengineered red blood cells (NERBCs) by an environmentally friendly method by using red blood cells as the raw material and hemoglobin (Hb) embedded with ultrasmall hydroxyapatite (HAP,C a 10 (PO 4 ) 6 (OH) 2 )a st he functional BFC cathode material. The NERBCs showed greatly enhanced cell performance with high electrocatalytic activity,s tability, and selectivity.T he NERBCs maintained the original biological properties of the natural cell, while enhancing the catalytic oxygen reduction reaction (ORR) through the interaction between À OH groups in HAP and the Hb in RBCs.They also enabled direct electron transportation, eliminating the need for an electron-transfer mediator,a nd showed catalytic inactivity for glucose oxidation, thus potentially enabling the development of separator-free BFCs.Enzyme biofuel cells (EBFCs) [1] have attracted considerable attention as micro- [2] or even nanoscale power [3] sources for implantable biomedical devices,s uch as cardiac pacemakers, [4] implantable self-powered sensors, [5] and biosensors for monitoring physiological parameters. [6] There are two types of EBFCs,w hich differ in the operating mechanism;n amely, mediated electron transfer (MET) [7] and direct electron transfer (DET) [8] EBFCs.M ET EBFCs rely heavily on redox mediators to shuttle electrons between biocatalytic active sites and electrode surfaces,w hereas DET EBFCs enable electron transfer from the enzyme active sites directly to the electrode. [9] In either case,t he other electrode (cathode) requires an oxygen-reduction catalyst, such as laccase [10] or bilirubin oxide (BOD), [11] to facilitate the oxygen reduction reaction (ORR). Unfortunately,i ng eneral, the current catalysts under investigation show very low catalytic performance as well as poor adhesion to the electrode surface. Such drawbacks drastically limit the practical application of EBFCs. [12] Although approaches such as electrode nanomodification, [1b] enzyme immobilization, [13] and redox-mediator addition [14] have been intensively investigated to facilitate electron transfer between enzymes and electrodes,t hey usually face some challenges,s uch as avoiding the deformation and inactivation of enzymes, [15] preventing nanotoxicity, [16] or improving the stability of the cell. [17] As is well-known, the biosafety of nanomaterials synthesized in vitro for long-term operation in the body,i no ther words,t he use of invasive, external, and foreign (relative to the nature of the cell) nanomaterials,i sc ontroversial, for many reasons,i ncluding their unexpected migration and accumulation. [18] Nanobioengineering, [19] which has already seen great success in the fields of medicine,agriculture,environment, and electronic systems offers ap otential opportunity to tackle these challenges.I n situ biomineralization [20] processes...