The physiological microenvironment is the environment surrounding cells, including chemical, physical and mechanical conditions, as well as neighboring cells and the extracellular matrix [1], [2]. The cellular microenvironment is achieved through the synergistic action of multiple signal pathways, with the presence of a variety of receptor molecules on the cell surface, which can respond to different signals, such as the external environment of the cell, neighboring cells, and physical or chemical changes in the surrounding matrix [3], [4]. Thus, the cellular microenvironment leads to cellular morphology, directed migration, proliferation, or transformation. The formation and regulation of the cellular microenvironment is a complex system of interactions and constant feedback regulation [5]. The balance of the physiological microenvironment is crucial for the maintenance of tissue homeostasis, and has an extremely important influence on the behavior and function of cells, such as growth, differentiation, migration, and apoptosis [6], [7], [8]. In contrast, imbalance of the microenvironment is closely associated with the development of many diseases such as inflammation, fibrosis, and tumors. Moreover, in different tissues and organs, the properties of the microenvironment vary to suit the needs of specific cells [9], [10]. It is important to construct appropriate strategies to regulate the cellular microenvironment and treat different diseases.

Tumor microenvironment (TME) includes tumor cells, immune cells, and extracellular matrix, which together form a complex tumor ecosystem [11]. It exerts a significant influence on tumor initiation, progression, invasion, metastatic spread, and growth [12]. The TME possesses its own distinctive characteristics of hypoxia, acidity, high concentration of reactive oxygen species (ROS), high concentration of glutathione (GSH), high mesenchymal pressure, and immune cell infiltration, which markedly differs from those of normal tissues and plays a key role in tumor development and therapy [13], [14], [15], [16]. Modulation of the tumor physiological microenvironment is a key strategy in tumor therapy [17]. Comprehensive interventions targeting different components and mechanisms in the TME can notably enhance therapeutic efficacy. In exploring tumor therapies, features of hypoxia, acidity, and high concentration of ROS and GSH in the TME have been utilized to design nano delivery systems [18], [19], [20]. These systems can be in specific activated to release, enable controlled spatial transport, and increase drug concentration at the tumor site to improve efficacy. In addition, newly reported work suggests that the nanosystems can also mimic enzyme activity to remodel the TME to regulate cellular homeostatic imbalances, which demonstrating unlimited potential for disease prevention and treatment [21], [22], [23]. The development of nanosystems responding to specific stimuli in the TME and combination with various advanced treatments such as chemotherapy, photothermal therapy, and photodynamic therapy are significant for curing of tumors, which will provide new options for patients [24].

In recent years, nanozymes have attracted much attention [25], [26]. Since the first report on nanozymes in 2007, a large number of researchers have dedicated to nanozymes-related researches and achieved many breakthroughs [27], [28], [29]. Nanozymes are powerful complements of natural enzymes and are considered to replace natural counterparts. Studies have shown that nanozymes take the advantages of high activity, stability, modifiability, and cheapness [30], [31], [32]. The development of novel nanosystems that enabling to effectively mimic enzyme activity and alter the TME to treat tumors is of great significance [33], [34], [35], [36], [37], [38]. Although many nanozymes have been applied in the therapeutic of diseases, studies related to the development of biomineralized fully active nanozymes and their application to the treatment of tumors have rarely been reported.

Herein, we developed a multifunctional fully active biomineralized nanoparticles (CaCO3@Pd@C) for intervening in microenvironment and efficient treatment of tumor (Scheme 1). The CaCO3@Pd@C was obtained by a simple in situ reaction to obtain the CaCO3@PDA-Pd2+ precursors, then they were annealed to obtain the biomineralized nanosystem. During the procedure for synthesis of precursors, the reaction substrates were reacted in situ generation and polymerization via a Stöber-like method. This CaCO3@Pd@C is a fully active with three different functions. It has the inner core of CaCO3 nanomaterials, which can consume the acid, the intermediate layer of Pd metallic with good peroxidase-like enzyme catalytic activity, and the outer sphere of porous carbon, which not only protects the calcium carbonate and the enzyme-like catalytic center, but also has a very good photo-thermal transcription effect. In vitro and in vivo experiment results shown that the fully active CaCO3@Pd@C can intervening in the complex tumor microenvironment and rapidly induce tumor cell apoptosis.