Long-acting lipid-based nanomedicines: rethinking from structure-based rational design to in vivo fate evaluation.

Long-acting lipid-based nanomedicines (LaLBNs) aim to sustain therapeutic effect through prolonged exposure and controlled drug release. However, extended circulation does not always translate into improved clinical outcomes. For instance, polyethylene glycol (PEG)-modified liposomes show enhanced pharmacokinetic (PK) parameters such as half-life and area under the curve, yet their benefits, as observed with Doxil®, often fail to meaningfully surpass free doxorubicin. This discrepancy arises because standard PK measurements quantify total drug concentration, which combines both of the encapsulated inactive drug and bioavailable released drug. True therapeutic longevity hinges not on carrier persistence in blood, but on the spatiotemporal pattern of active drug availability at the target site. Therefore, a rational evaluation and understanding of the in vivo journey of nanocarriers are essential prerequisites for achieving effective therapy. In this review, we summarize the rational design of LaLBNs and systematically evaluate the in vivo fates using an absorption, distribution, metabolism, and excretion framework. We critically assessed existing analytical methods and proposed strategies that integrate both temporal and spatial dimensions to better capture the dynamic fate of LaLBNs. By reframing LaLBNs as active biological entities rather than inanimate carriers, we advocate a paradigm shift from merely prolonging circulation to comprehensively orchestrating the entire delivery process, thereby narrowing the gap between nanocarrier design and therapeutic performance.