Drug delivery systems (DDSs) can improve the bioavailability of drugs, prolong the circulation time in the bloodstream and abate side effects [1], [2], [3], [4], [5], [6], [7], [8]. Commonly used DDSs include polymer micelles, liposomes, dendrimers, carbon nanotubes and silicon nanoparticles. Among them, hollow mesoporous silica nanoparticles (HMSNs) are promising and efficient DDSs due to their large drug loading cavities and permeable mesoporous shell structures [9], [10], [11], [12], [13]. Unfortunately, the application of bare HMSNs is limited due to their poor solubility in blood and body fluids, easy absorption by macrophages, and unintelligent release behaviors [14]. Surface modification with water-soluble particles, which are called capping agents [15], [16], [17], [18], [19], [20], [21], [22], is the most commonly used method to solve the above problems and abundant silicon hydroxyl groups on the surface make it easy to realize [23], [24], [25].

Various species, including inorganic nanoparticles, organic molecules and biomolecules, have been selected as capping agents to enhance the dispersity of HMSNs. The linkages between capping agents and HMSNs, together with the capping agents, may endow HMSNs sensitivities to external stimuli, such as pH, redox, temperature and enzymes [26], [27], [28], [29], [30]. The tumor site shows different physical, chemical and biological properties from normal tissues, such as slightly acidic pH, slightly higher temperature and higher H2O2 concentration [31], [32], [33], [34]. Smart HMSNs may intelligently distinguish the difference and achieve controlled release [35], [36], [37], [38]. Poly (N-vinyl caprolactam) (PNVCL), a thermosensitive polymer with lower critical solution temperature (LCST) slightly lower than normal physiological temperature (T = 37 °C), is a commonly used capping agent to endow HMSNs thermosensitivity. Carbon dots (CDs) are novel fluorescent nanoparticles with spherical morphology and particle size less than 10 nm. Their excellent water solubility and moderate size present possibilities to be used as capping agents. pH sensitive linkers (Imine, acetal, hydrazone, etc.), which will fracture in slight acidic tumor site and result in intelligent release of drugs, are commonly used to tether HMSNs and capping agents.

As an endogenous gaseous biological mediator, nitric oxide (NO) is crucial in physiology and pathophysiology. NO has shown significance in tumor progression related to concentration [39]. Tumor growth can be accelerated at lower NO concentrations, while larger NO concentrations result in tumor cells apoptosis (>1 µM) [40]. In addition, co-delivery of NO and anticancer drugs can significantly enhance the antitumor effects. CDs with guanidine-rich surfaces can be used as endogenous NO donors, and release NO at high H2O2 concentration conditions of tumor site [41].

Herein, novel multiple sensitive HMSNs based DDSs with mixed shells (CDs/[email protected]) were prepared, wherein CDs and PNVCL were the blend shells and acid-sensitive Schiff base bonds were between HMSNs and shells [42]. At room temperature, the PNVCL was soluble and the mesopores of the HMSNs were in open states. Therefore, anticancer drug-doxorubicin (DOX) could be transported freely through mesoporous pores. When the drug loaded DDSs (CDs/[email protected]) were injected into the blood stream (pH = 7.4, T = 37 °C), PNVCL chains collapsed and the drugs were encapsulated inside. CDs acted as "caps" and their fine water solubility make the particles disperse well in blood instead of gathering. The acid-liable Schiff base bonds between the HMSNs and the shells endow the DDSs pH sensitivity, while the H2O2 sensitivity is given by CDs, which were prepared from arginine and rich in guanidine on surface [43]. At the slight acidic condition of tumor site, the Schiff base bonds break and the shells (CDs/PNVCL) fall off from HMSNs, resulting in opening of the pores and releasing of guest molecules. The high H2O2 concentration condition of tumor site lead to the release of NO [44], [45], [46], [47]. Higher NO concentrations may result in tumor cells apoptosis (Fig. 1). In sum, CDs/[email protected] were sensitive to temperature, pH, and H2O2 concentration. Drug loading could be successfully achieved and leakage in blood were restrain due to their thermosensitivity. Drug and NO were simultaneously released at acidic and high H2O2 concentration tumor site because of their pH and H2O2 sensitivity and they could both “kill” tumor cells. Moreover, the combination of drug and NO might have enhancive effects [48], [49], [50].