Biotherapeutics play a pivotal role in advancing the practice of precision medicine by providing effective treatment options for a wide range of diseases. However, their bioavailability in vivo is severely constrained by dense and complex biological barriers with individualized geometry. Herein, we present a Janus porous metamaterial (JPM) capable of generating directional microjets for robust and conformal biotherapeutics delivery across biological barriers. This JPM enables ultrasound energy harvesting and cavitation reinforcement, thereby facilitating continuous liquid jet generation. Multiple therapeutic agents, including proteins, polysaccharides, and nucleic acids, can cross various biological barriers within 1–5 min. Notably, this JPM enables unprecedented penetration of protein (albumin, 66.43 kDa) through a dense, 100 µm-thick biological barrier within just 3 min of mild ultrasound, demonstrating a superior delivery efficiency compared to conventional ultrasound-based methods. Besides, by adjusting the orientation of the porous layer of the JPM, circumferentially uniform gene delivery in blood vessels is demonstrated in rat models, enabling precise modulation on the inflammatory response and vascular regeneration after injury. Furthermore, the integration of the metamaterial with balloons has been developed to facilitate versatile endoluminal delivery. Taken together, this JPM holds promising potential for biotherapeutics delivery in deep tissues.