Calreticulin (CRT) is a ubiquitously expressed and evolutionarily conserved protein primarily located in the endoplasmic reticulum (ER), where it participates in various cellular processes, including protein folding, calcium homeostasis, antigen-loading, and immune system regulation (Fucikova et al., 2021). Additionally, CRT has a critical extracellular function as an “eat-me” signal on the surface of stressed or dying cells. The externalized CRT, or “ecto-CRT,” acts as a phagocytic signal for macrophage-mediated removal of both viable and apoptotic and cancerous cells. Ecto-CRT also influences the immunogenicity of dying cells, which is one of the three major hallmarks that lead to the successful induction of immunogenic cell death (ICD) in cancer and infectious diseases (Galluzzi et al., 2017, Liu et al., 2021b, Liu et al., 2021c, Obeid et al., 2007). The other two hallmarks are the release of adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1) from the dying cells. This is because ecto-CRT facilitates tumor antigen uptake and presentation by antigen-presenting cells, such as dendritic cells, which is essential for initiating an immune response (Fucikova et al., 2020, Fucikova et al., 2021, Galluzzi et al., 2017, Galluzzi et al., 2023, Gardai et al., 2005). In addition, ecto-CRT is recognized by murine Natural Killer (NK) cells via NKp46 to enhance degranulation and cytokine secretion of tumor-infiltrating NK cells (Sen Santara et al., 2023). There is also clinical evidence that ecto-CRT expression is associated with T-cell infiltration in human colon cancer, underscoring its relevance in anti-tumor immunity (Obeid et al., 2007, Peng et al., 2010). The ecto-CRT-mediated phagocytosis is facilitated by binding and activating the LDL-receptor-related protein (LRP/CD91). This CRT/LRP interaction also displaces the LRP receptor-associated protein (RAP/LRPAP1), suggesting potential binding sites in complement-type repeats (CRs) in LRP’s extracellular region. However, the specific binding domains and underlying mechanisms are not fully elucidated (Feng et al., 2015, Gardai et al., 2005). In light of these findings, this study seeks to harness the natural “eat-me” functionality of ecto-CRT, proposing its application in novel bio-derived strategies aimed at enhancing the delivery efficiency of liposomal formulations, which are commonly used for therapeutic delivery. We explore the possibility that leveraging ecto-CRT's natural signaling pathways may offer a targeted approach to enhance delivery efficiency to antigen-presenting cells, e.g., dendritic cells, potentially improving the efficacy of therapeutic agents. Our study aims to leverage the intrinsic “eat-me” properties of ecto-CRT as a targeted means to enhance the delivery and immunogenic efficacy of therapeutic agents, particularly to antigen-presenting cells such as dendritic cells. By integrating the function of ecto-CRT, this study explores its potential for advancing bio-derived drug delivery methodologies.