<p>The design of effective drug nanocarriers requires the prevention of adverse biological interactions such as immune activation and cytotoxicity, making superior biocompatibility a critical determinant for clinical success. While existing reviews predominantly focus on the therapeutic applications of nanomedicines, systematic analyses of biocompatibility optimization strategies remain scarce. To address this gap, we present a review of three primary approaches for constructing biocompatible nanocarriers: (1) inert-material-based frameworks, (2) polymer surface engineering techniques, and (3) biomimetic functionalization methodologies. By evaluating the structural designs and biological mechanisms of commonly employed materials, we elucidated how these strategies leverage inherent material properties and biological interaction principles to regulate biocompatibility. Furthermore, we analyzed the advantages and limitations of each approach, offering guidance for selecting the optimal biocompatibility enhancement methods. This work not only synthesizes current advancements in biocompatible nanocarrier development but also provides actionable insights to advance nanomedicine research and clinical translation.</p> Graphical Abstract <p></p>