Cancer nanomedicines were initially envisioned as magic bullets, travelling through the circulation to target tumors while sparing healthy tissues the toxicity of classic chemotherapy. However, currently there are only 21 cancer nanomedicines approved for clinical use worldwide [1], with only 14 being systematically administered nanomedicines. The majority of approved nanomedicines predominantly rely on liposomal formulations of previously authorized small-molecule chemotherapeutics [2]. Although compared with traditional chemotherapy, these nanomedicines reduce side effects and improve the quality of life of patients, most nanomedicines fail to improve the therapeutic effect. In phase III clinical trials, merely 14% nanomedicines present potential efficacy [3]. The lack of comprehensive knowledge regarding the interactions between nanomedicines and the intricate in vivo environment (nano–bio interactions) could be responsible for a significant disparity between the advancements made in laboratory nanomedicine and their actual clinical effectiveness.

Systemically administered nanomedicine faces five-step cascade on its travel to a tumor, including blood circulation, tumor accumulation, tumor penetration, cell internalization and drug release [4]. The overall efficiency of drug delivery relies on the effectiveness of every step in the process. Tumor infiltration is regarded as a significant drawback of the nanoparticles-based drug delivery among the aforementioned five stages. Overall, the interaction between tumor and nanoparticles (nano–bio interactions) significantly influence tumor penetration. Compared with normal tissues, the overwhelming complexity of tumor microenvironment is the mean reason to cause the extremely low delivering efficiency of nanomedicines to the tumor, leading to only 0.7% (median) of intravenous nanomedicine enter the tumor stroma [5] and only 0.0014% injected dose delivered to targeted cancer cells [6]. Attempts have been undertaken to improve the penetration and accumulation of nanomedicines in the solid tumor. Nonetheless, inadequate infiltration and accumulation of curative agents is recognized as the primary factor leading to the failure of nanomedicines clinical translation [7].

The tumor microenvironment is composed of extracellular matrix (ECM) and various cell types, including immune cells, fibroblasts, endothelial cells, and adipocytes, which collectively support the development of tumors [8]. ECM, a dynamic network supporting connective tissue, is not merely a passive observer, but instead plays a crucial role in promoting tumor initiation, malignant progression, metastasis, and resistance to treatment. As a physical barrier that hindering the penetration (systemic administration) or spread (intratumor administration) of nanomedicines, targeting the ECM is potential to enhance nanomedicines diffusion and accumulation in solid tumors. Additionally, the properties of nanoparticles (i.e., size, shape and surface characteristics) are the key parameters to determine tumor penetration efficiency. Hence, a comprehensive grasp of the constituents and characteristics of ECM is vital for the advancement of nanomedicine and the revelation of the intratumoral destiny of nanomedicines.

In this review, we initially review the main alterations of ECM during tumor progression, and discuss intratumoral biophysical obstacles to cancer nanomedicines, with a specific emphasis on the impact of mechanical or physical characteristics of ECM, such as flexibility or rigidity, on the destiny of nanoparticles within the tumor. Then, we elaborate on two directions to enhance the transportation and dispersion of nanomedicines in tumors by employing advanced techniques for nanoformulation design, aiming to fulfill its original objectives. Ultimately, the potential future challenges and outlook of nanocarrier delivery systems is dissected.