Nanomedicine Disrupts Stromal Barriers to Augment Drug Penetration for Improved Cancer Therapy†

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Comprehensive SummaryTumor stroma composing diverse extracellular matrixes (ECM) and stromal cells shapes a condensed physical barrier, which severely hampers the efficient accessibility of nanomedicine to tumor cells, especially these deep‐seated in the core of tumor. Such barrier significantly compromises the antitumor effects of drug‐loaded nanomedicine, revealing the remarkable importance of disrupting stromal barrier for improved tumor therapy with deep penetration ability. To achieve this goal, various nanoparticle‐based strategies have been developed, including direct depleting ECM components via delivering anti‐fibrotic agents or targeting stromal cells to suppress ECM expression, dynamic regulation of nanoparticles’ physicochemical properties (i.e., size, surface charge, and morphology), mechanical force‐driven deep penetration, natural/biomimetic self‐driven nanomedicine, and transcytosis‐inducing nanomedicine. All these nanostrategies were systemically summarized in this review, and the design principles for obtaining admirable nanomedicine were included. With the rapid development of nanotechnology, elaborate design of multifunctional nanomedicine provides new opportunities for overcoming the critical stromal barriers to maximize the therapeutic index of various therapies, such as chemotherapy, photodynamic therapy, and immunotherapy. Key ScientistsIn 2006, Chan et al. demonstrated that the size and shape of nanoparticles were important for biomedical applications, such as intracellular delivery rate and tissue penetration. In addition, the degradation of the structural collagen was confirmed to increase the diffusion of nanoparticles and macromolecules by Davies et al. in 2010. These findings reveal the importance of chemophysical properties of nanoparticles in determining their diffusion and the critical roles of stromal barrier in hindering nanoparticles penetration. On the basis of this, photoswitchable nanoparticles were developed by Kohane et al. for triggered tissue penetration and efficient drug delivery. In 2015, Nie et al. reported the targeted depletion of cancer‐associated fibroblasts by peptide assembly for enhanced antitumor drug delivery. In 2019, Shen et al. proposed the transcytosis strategy to promote the tumor penetration of nanoparticles. Very recently, Luo et al. reported the specific reversing of the biological function of cancer‐associated fibroblasts to suppress the generation of stromal matrix, greatly increasing the drug perfusion in tumor tissue. All these strategies fueled the design and construction of function‐specific nanoparticles for tumor therapy.