Cancer remains a highly lethal disease worldwide, primarily due to its intrinsic characteristics that complicate curability, its propensity for metastasis, and the likelihood of recurrence [1]. Accurate diagnosis, effective treatment, and prognostic evaluation are essential for improving patient survival rates and quality of life [2]. In light of these critical considerations, advanced tumor treatment platforms employing imaging modalities such as computed tomography (CT) [3], magnetic resonance imaging (MRI) [4], and positron emission tomography (PET) [5] have been successfully developed in recent years. These platforms not only effectively eliminate tumor cells but also enable the tracking of drug distribution, monitor the drug release process, and evaluate the efficacy of cancer therapies [6], [7]. However, existing diagnostic and therapeutic agents face significant challenges including limited tumor targeting capabilities, inadequate dynamic monitoring, and suboptimal treatment efficacy-factors that hinder their further clinical application [8]. Therefore, there is an urgent need to develop more precise, efficient, and safe integrated diagnostic and therapeutic strategies that address the limitations inherent in conventional approaches to cancer diagnosis and management.

CT imaging has been widely used in clinical practice for tumor screening and staging, owing to its advantages including high resolution, three-dimensional imaging, reduced radiation exposure, and rapid acquisition of images compared to MRI and PET [9], [10], [11]. 2, 3, 5-triiodobenzoic acid (TIBA), a novel CT contrast agent characterized by high iodine content, demonstrates significant attenuation of X-rays and enhances the CT imaging quality of tissues [12]. Additionally, it promotes tumor cell apoptosis via the generation of intracellular reactive oxygen species (ROS) [13]. Nevertheless, the inadequate water solubility and suboptimal tumor selectivity significantly impede its clinical application. Theranostic nanomedicines by integrating diagnostic and therapeutic agents into nanoparticles, have been recently paid tremendous attention owing to their superior advantages such as increased solubility, improved pharmacokinetics, passive tumor target and minimal side effects, but fail to significantly enhance tumor accumulation due to their insufficient tumor selectivity and low drug loading, resulting in unsatisfactory theranostic outcome [14], [15]. Notably, pH-triggered dynamic nanomedicines can significantly improve tumor selectivity via tumoral extracellular specific changes in physical and chemical properties such as detachable PEGylation [16], charge reversal [17] and size transition [18]. We have established a series of highly selective dynamic nanomedicines with these physicochemical properties by using pH-ultra-sensitive orthoester (OE) linkages [19]. They not only enhance drug accumulation at tumor site, but also facilitate targeted drug release within tumor cells. Thus, the incorporation of OE linkages for the chemical conjugation of TIBA possesses significant potential for the development of a small molecule dynamic theranostic nano-prodrug aimed at increasing drug loading as well as enhancing diagnostic precision and treatment efficacy [20].

Doxorubicin (DOX), a widely utilized anthracycline in clinical chemotherapy, not only induces DNA cross-linking and inhibits topoisomerase II activity but also disrupts normal mitochondrial function, and elevates free radical levels within tumor cells [21]. Furthermore, it has the capacity to activate cytotoxic CD8 T cells, facilitating the elimination of tumor cells in conjunction with TIBA [22], [23]. Besides, its structure contains a heteroaromatic ring and an amino group, which can strongly interact with an aromatic ring and a carbonyl group in the structure of OE-linked TIBA via π-π stacking and hydrogen bonding interactions, therefore self-assembling into a highly selective theranostic nanomedicine with dynamic size transition, amino protonation, and combination effect between TIBA and DOX (Fig. 1).