The extraordinary growth and progression of tumor require enormous nutrient and energy. Unregulated behaviors of cancer cell progressing and persistently change of tumor microenvironment (TME) which acts as the soil for cancer growth and metastasis are the ubiquitous features. The tumor microenvironment exhibits some unique features which differ with the normal tissues. While the nanoparticles get through the blood vessel leakage, they encounter immediately and interact directly with these microenvironment factors. These factors may inhibit the diffusion of nanoparticles from penetrating through the tumor, or induce the dissociation of nanoparticles. Different nanoparticles encountered with different intratumoral microenvironment factors end up in different way. Therefore, in this review, we first briefly introduced the formations, distributions, features of some intratumoral microenvironment, and their effects on the tumor progression. They include extracellular matrix (ECM), matrix metalloproteinases (MMPs), acidic/hypoxia environment, redox environment, and tumor associated macrophages (TAMs). We then exemplified how these factors interact with nanoparticles and emphasized the potentials and challenges of nanoparticle-based strategies facing in enhancing intratumoral penetration and tumor microenvironment remodeling. We hope to give a simple understanding of the interaction between these microenvironment factors and the nanoparticles, thus, favors the designing and constructing of more ideal functional nanoparticles. Display omitted