The tumor penetration of nanomedicines constitutes a great challenge in the treatment of solid tumors, leading to the highly compromised therapeutic efficacy of nanomedicines. Here, we developed small morph nanoparticles (PDMA) by modifying polyamidoamine (PAMAM) dendrimers with dimethylmaleic anhydride (DMA). PDMA achieved deep tumor penetration via an active, energy-dependent, caveolae-mediated transcytosis, which circumvented the obstacles in the process of deep penetration. PDMA remained negatively charged under normal physiological conditions and underwent rapid charge reversal from negative to positive under acidic conditions in the tumor microenvironment (pH < 6.5), which enhanced their uptake by tumor cells and their deep penetration into tumor tissues and . The deep tumor penetration of PDMA was achieved mainly by caveolae-mediated transcytosis, which could be attributed to the small sizes (5-10 nm) and positive charge of the morphed PDMA. studies demonstrated that PDMA exhibited increased tumor accumulation and doxorubicin-loaded PDMA (PDMA/DOX) showed better antitumor efficacy. Overall, the small morph PDMA for enhanced deep tumor penetration via caveolae-mediated transcytosis could provide new inspiration for the design of anticancer drug delivery systems.