Deep Tumor Penetration Using Nanoparticle Delivery Systems: Programmed Design Strategies and Emerging Evaluation Platforms

The complex architecture of solid tumors, including dense extracellular matrix and abnormal vasculature, impedes effective nanoparticle (NP) delivery. Conventional NPs often fail to penetrate deeply due to their fixed size, rapid clearance, and poor tumor retention. Unlike previous reviews that focus solely on physicochemical properties, this article critically evaluates "programmed" delivery strategies that dynamically adapt to physiological barriers. Size-transformable nanocarriers offer a promising solution by remaining large during circulation to exploit the enhanced permeability and retention (EPR) effect, then shrinking in response to tumor-specific stimuli (eg, low pH, high glutathione, or enzymatic activity), thereby improving tumor penetration and drug release This review highlights recent advances in overcoming these obstacles, with a focus on programmed delivery strategies NPs with a size-switching technique degrade upon reaching the tumor site, allowing for deeper penetration. Surface modification enhances interactions with the tumor microenvironment (TME), whereas ligands improve target selectivity and tumor cell uptake, and altering the NP form improves their delivery and distribution within tumors. Uniquely, the review bridges the gap between design and evaluation by discussing emerging experimental platforms such as 3D tumor models and microfluidic chips. Finally, it examines the growing role of artificial intelligence (AI) and in silico modeling in optimizing NP design, offering insights into precision nanomedicine.