**Abstract:** A research team led by Professor Rui Kuai from the School of Pharmaceutical Sciences at Tsinghua University has developed an innovative "onion-like" multi-layer liposome, termed HLHC (HA-lipid hybrid nanoparticles encapsulating cGAMP), by physically cross-linking hyaluronic acid (HA) and lipid molecules. This study, published in the journal *ACS Nano* on October 17, addresses the challenges associated with the systemic delivery of small molecule STING (Stimulator of Interferon Genes) agonists, specifically cGAMP, which are critical for enhancing anti-tumor immune responses. STING agonists, such as cGAMP, are negatively charged hydrophilic small molecules that can stimulate the production of type I interferons by activating antigen-presenting cells (APCs) within tumor tissues. This activation is pivotal for boosting anti-tumor immune responses. However, these molecules are prone to rapid clearance from the body and have low efficiency in crossing biological membranes, making it difficult to deliver them effectively to the cytoplasm of APCs. Previous attempts to improve delivery efficiency using various lipid or polymer nanoparticles have been limited by either premature drug release in the bloodstream or poor cytoplasmic delivery in target cells. Inspired by the multi-layer structure of onions, the team hypothesized that creating a multi-layer liposome using HA and lipid molecules could enhance stability while maintaining high cytoplasmic delivery efficiency. This approach avoids the use of chemical cross-linking agents, which can pose safety risks and complicate the manufacturing process. Using a microfluidic device, the team was able to produce HLHC nanoparticles with a particle size below 100 nanometers, suitable for systemic administration. Electron microscopy confirmed the "onion-like" cross-sectional structure of HLHC. In vitro experiments demonstrated that HLHC exhibited superior stability and sustained release properties compared to conventional liposomal cGAMP (LC). This enhanced stability allowed HLHC to deliver a higher amount of cGAMP to the cytoplasm, leading to a more significant activation of the STING pathway and a marked increase in type I interferon secretion. In vivo studies further showed that the multi-layer structure of HLHC significantly prolonged the circulation time of cGAMP, increased its accumulation in tumor sites, and effectively activated the STING pathway in intra-tumoral APCs. A single intravenous injection of HLHC was sufficient to trigger a robust anti-tumor immune response in mice, resulting in the regression of established subcutaneous MC38 tumors. When combined with checkpoint inhibitors, HLHC also demonstrated the ability to regress B16F10 melanoma tumors. Importantly, treated mice developed long-lasting immune memory, reducing the risk of tumor recurrence. This research provides a novel solution to the longstanding issue of balancing nanoparticle stability and efficient cytoplasmic delivery in systemic drug administration. The simplicity and ease of HLHC production make it a promising platform for the delivery of other small molecules, potentially broadening its application in cancer immunotherapy. The study was supported by several national and university-level programs, including the National High-Level Talent Program for Young Scholars, the National Natural Science Foundation of China, the Tsinghua-Peking Center for Life Sciences, Tsinghua University's Frontier Interdisciplinary Research Program, and the Dushu Program. **Key Contributions:** - **Rui Kuai** (Corresponding Author) - **Jinzhuo Yu** (First Author, Ph.D. graduate) - **Xinyan Li, Nan Sun** (Ph.D. students) - **Junyao Li** (Postdoctoral Fellow) - **Saile Li** (Professor, School of Life Sciences, Tsinghua University) - **Cheng Peng** (Ph.D. student, School of Life Sciences, Tsinghua University) - **Jia Yi Huang** (Undergraduate, School of Pharmaceutical Sciences, Tsinghua University) The research findings highlight the potential of HLHC as a next-generation drug delivery system, capable of delivering STING agonists with high efficiency and safety, thereby opening new avenues for cancer treatment and prevention.