Chemotherapy drugs have been known as the mainstay of cancer treatment; however, they have inevitable side effects when used in isolation. Drug-loaded nanosystems represent a breakthrough drug delivery platform that enhances the treatment index of chemotherapy in cancer treatment; further, it compensates for the deficiency of body toxicity and significantly enhances antitumor effects. Given that designing biosafe nanodrugs requires nontoxicity of carriers, novel polymers, synthesized from natural products, with good biocompatibility and biodegradation are the preferred drug carriers. Ferulic acid (FA) derived from plants can be chemically modified to form poly(ferulic acid) (PFA) with reassuring biosafety. PFA-loading doxorubicin (DOX) was properly self-assembled into stable PFA@DOX nanoparticles (NPs), which released payloads continuously under slightly acidic conditions in vitro, ensuring effective drug delivery in acidic tumor microenvironments. In vivo antitumor therapy showed that the PFA nanocarriers could promote accumulation and retention at the tumor site for superior tumor suppression, while the PFA@DOX NPs reduced the physical toxicity of free DOX, thereby, improving safety. Therefore, such drug-loaded NPs can exert considerable influence over an antitumor action for potential clinical translation in the future.