Stem cell-derived organoids are emerging as living therapeutics for repairing or replacing damaged tissues and organs, offering new opportunities for regenerative medicine. However, their clinical translation remains limited by immune rejection, insufficient functional integration, and low manufacturing throughput. In this review, we summarize recent advances in engineering organoids toward implantable living therapeutics by examining how hydrogel engineering, microfluidic chips, three-dimensional bioprinting, and synthetic biology overcome key translational barriers and facilitate the in vivo application of organoids. We further discuss the existing regulatory frameworks supporting the clinical translation of organoid-based therapies. Current evidence indicates that these bioengineering strategies enhance graft survival, tissue integration, and therapeutic efficacy through complementary mechanisms, including immunomodulatory signals, biomimetic microenvironments, hierarchical tissue architectures, and programmable cellular functions. Importantly, engineered organoids have been successfully applied to restore hair-bearing skin, repair colonic epithelial continuity, bridge critical-size bone defects, and correct metabolic disorders. Despite these advances, significant challenges remain in quality-control standardization, scalable manufacturing, regulatory harmonization, and long-term safety assessment. Future studies integrating artificial intelligence (AI) and intelligent living devices are warranted to facilitate high-fidelity manufacturing, quality inspection, real-time monitoring, and closed-loop therapeutic regulation in clinical practice. Collectively, engineered organoids represent a promising frontier for new-generation transplantation and regenerative medicine.

Genetically engineered bacteria have aroused attention as micro-nano drug delivery systems in situ. However, conventional designs of engineered bacteria usually function constantly or autonomously, which might be non-specific or imprecise. Therefore, designing and optimizing in situ control strategy are important methodological progress for therapeutic researches of intestinal engineered bacteria. Here, a micro-nano optogenetic system based on probiotic was developed combining microelectronics, nanotechnology, and synthetic biology to achieve in situ controllable drug delivery. Firstly, optogenetic engineered Lactococcus lactis was orally administrated in the intestinal tract. A wearable optical device was designed to control optical signals remotely. Then, L. lactis could be customized to secrete peptides according to optical signals. As an example, optogenetic L. lactis system can be constructed to secrete glucagon-like peptide-1 (GLP-1) under the control of the wearable optical device to regulate metabolism. To improve the half-life of GLP-1 in vivo, Fc-domain fused GLP-1 was optimally used. Using this strategy, blood glucose, weight, and other features were well controlled in rats and mice models. Furthermore, upconversion microcapsules were introduced to increase the excitation wavelength of the optogenetic system for better penetrability. This strategy has biomedical potential to expand the toolbox for intestinal engineered bacteria.

Protein degradation technology, which is one of the most direct and effective ways to regulate the life activities of cells, is expected to be applied to the treatment of various diseases. However, current protein degradation technologies such as some small-molecule degraders which are unable to achieve spatiotemporal regulation, making them difficult to transform into clinical applications. In this article, an upconversion optogenetic nanosystem was designed to attain accurate regulation of protein degradation. This system worked via two interconnected parts: 1) the host cell expressed light-sensitive protein that could trigger the ubiquitin-proteasome pathway upon blue-light exposure; 2) the light regulated light-sensitive protein by changing light conditions to achieve regulation of protein degradation. Experimental results based on model protein (Green Fluorescent Protein, GFP) validated that this system could fulfill protein degradation both in vitro (both Hela and 293T cells) and in vivo (by upconversion optogenetic nanosystem), and further demonstrated that we could reach spatiotemporal regulation by changing the illumination time (0-25 h) and the illumination frequency (the illuminating frequency of 0-30 s every 1 min). We further took another functional protein (The Nonstructural Protein 9, NSP9) into experiment. Results confirmed that the proliferation of porcine reproductive and respiratory syndrome virus (PRRSV) was inhibited by degrading the NSP9 in this light-induced system, and PRRSV proliferation was affected by different light conditions (illumination time varies from 0-24 h). We expected this system could provide new perspectives into spatiotemporal regulation of protein degradation and help realize the clinical application transformation for treating diseases of protein degradation technology.