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Abstract Persistent pulmonary air leaks contribute to prolonged hospitalization. While existing hydrogel-based sealants can be used to stop air leaks, they may lack the high elasticity needed to accommodate lung deformation and mechanical cohesion. We developed an injury-conforming sealant with an adhesion layer underneath a customized bioprinted reinforcement layer. The leak- and rupture-pressure tests demonstrated substantial improvement in adhesive and cohesive strengths of the dual-layer sealant compared to single-layer control. We also developed a computer vision-guided tracking method to quantitatively assess sealant–tissue compliance during ventilation in ex vivo swine lungs. When used to repair air leaks on ventilated swine lungs, the sealant maintained structural integrity during cyclic ventilation, exhibiting a dynamic strain of 13.4% ± 0.8% relative to 19.7% ± 0.3% in the underlying tissue. The sealant repaired the leak and restored peak-inspiratory pressure (PIP) to baseline levels (PIPNative: 30.0 ± 0.8 cmH2O; PIPInjured: 25.3 ± 0.6 cmH2O; PIPSealed: 29.5 ± 1.3 cmH2O). Collectively, our findings demonstrate that the injury-conforming dual-layer sealant effectively seals pulmonary air leak while accommodating cyclic tissue deformation during ventilation. 

Abstract Ionizable lipid nanoparticles (LNPs) are pivotal in combating COVID‐19, and numerous preclinical and clinical studies have highlighted their potential in nucleic acid‐based therapies and vaccines. However, the effectiveness of endosomal escape for the nucleic acid cargos encapsulated in LNPs is still low, leading to suboptimal treatment outcomes and side effects. Hence, improving endosomal escape is crucial for enhancing the efficacy of nucleic acid delivery using LNPs. Here, a mechanical oscillation (frequency: 65 Hz) is utilized to prompt the LNP‐mediated endosomal escape. The results reveal this mechanical oscillation can induce the combination and fusion between LNPs with opposite surface charges, enhance endosomal escape of mRNA, and increase the transfection efficiency of mRNA. Additionally, cell viability remains high at 99.3% after treatment with oscillation, which is comparable to that of untreated cells. Furthermore, there is no obvious damage to mitochondrial membrane potential and Golgi apparatus integrity. Thus, this work presents a user‐friendly and safe approach to enhancing endosomal escape of mRNA and boosting gene expression. As a result, this work can be potentially utilized in both research and clinical fields to facilitate LNP‐based delivery by enabling more effective release of LNP‐encapsulated cargos from endosomes.