Adaptive nanocarriers targeting tumor systemic intelligence: A paradigm to overcome systemic barriers in precision drug delivery

Biological barriers remain a primary limitation to effective cancer therapy, restricting drug delivery, distribution, and therapeutic efficacy across tumor sites. These barriers arise from a complex and dynamic interplay between tumor- and host-derived factors, including abnormal vasculature, dense extracellular matrices, immune clearance, and spatiotemporal heterogeneity within the tumor microenvironment. Increasing evidence suggests that these components operate as an integrated and adaptive network. Here, we conceptualize this network as "tumor systemic intelligence," which enables tumors to sense and respond to therapeutic and physiological perturbations by reinforcing delivery barriers and limiting drug access. Conventional nanomedicine strategies, often designed to overcome individual barriers, have shown limited success in addressing this coordinated system. To overcome these limitations, we propose "adaptive intelligence" as a design paradigm for next-generation nanocarriers. In this framework, nanocarriers are engineered as responsive systems capable of sensing microenvironmental cues and dynamically modulating their physicochemical properties to navigate multiple, evolving barriers during systemic circulation and tumor penetration. We discuss key design strategies for adaptive nanocarriers, including programmable control over size, shape, surface charge, and bioactive interfaces, enabling improved circulation stability, enhanced transvascular transport, deeper tumor penetration, and reduced immune recognition. We further examine how these systems can modulate or bypass critical barriers such as extracellular matrix density, abnormal perfusion, and cellular uptake limitations. Integration with external physical stimuli is also considered to further enhance barrier penetration and delivery efficiency. Despite promising advances, clinical translation remains limited by challenges including nanocarrier safety, immunogenicity, and the complexity of tumor-host interactions. This review highlights emerging opportunities and design principles for adaptive nanocarriers that effectively navigate biological barriers, with the goal of improving drug delivery and therapeutic outcomes in cancer treatment. Importantly, the concepts of systemic intelligence and adaptive intelligence are intended as conceptual frameworks to guide the rational design of next-generation nanomedicines rather than as formal biological classifications.