Optogenetics has revolutionized neuroscience understanding by allowing spatiotemporal control over cell-type specific neurons in neural circuits. However, the sluggish development of noninvasive photon delivery in the brain has limited the clinical application of optogenetics. Focused ultrasound (FUS)-derived mechanoluminescence has emerged as a promising tool for in situ photon emission, but there is not yet a biocompatible liquid-phase mechanoluminescence system for spatiotemporal optogenetics. To achieve noninvasive optogenetics with a high temporal resolution and desirable biocompatibility, we have developed liposome (Lipo@IR780/L012) nanoparticles for FUS-triggered mechanoluminescence in brain photon delivery. Synchronized and stable blue light emission was generated in solution under FUS irradiation due to the cascade reactions in liposomes. In vitro tests revealed that Lipo@IR780/L012 could be triggered by FUS for light emission at different stimulation frequencies, resulting in activation of opsin-expressing spiking HEK cells under the FUS irradiation. In vivo optogenetic stimulation further demonstrated that motor cortex neurons could be noninvasively and reversibly activated under the repetitive FUS irradiation after intravenous injection of lipid nanoparticles to achieve limb movements.

Liposome-based drugs have emerged as highly successful nanomedicines for clinical applications owing to their excellent biocompatibility, biodegradability, and targeting effects. However, the lipids that play a crucial role in most liposome formulations are often engineered rather than natural phospholipids. From this perspective, we outlined the classification of engineered lipids based on their material chemistry, including charged, polymerconjugated, ligand-conjugated, and choline phosphate lipids. We also discussed their drug, gene, protein, and probe delivery applications. With the increasing requirements for the innovation of nano drug excipients by the Food and Drug Administration, attention to drug efficacy and side effects has increased in clinics, and the development of superior engineered lipids has become urgent. Therefore, we aim to provide a new idea for developing engineered lipids in which lipids can be engineered with minimal chemical structure changes to achieve maximum functions enhancement, with choline phosphate lipids being a favorable choice. In the future, novel engineered lipids and liposomes should be developed with more powerful functions and superior therapeutic safety, which will allow their utilization in the diagnosis and treatment of major diseases and be valuable for more clinical applications.