Magnetic nanoparticles such as the popular Fe₃O₄ nanoparticles also include other forms of ferrites and particles doped with Gd³⁺, Mn²⁺, etc., possess potential biomedical applications in magnetic resonance imaging (MRI) (Kim et al., 2011; Hu and Zhao, 2012; Lee et al., 2014), and magnetic targeted drug delivery and separation (Giri et al., 2005; Gao et al., 2009; Sahoo et al., 2014; Wang and Gu, 2015). However, pure Fe₃O₄ (or other iron oxide) nanoparticles have a strong tendency of aggregating and are instable over long periods of internal cycles, limiting their in-vivo biological usages (Liu et al., 2011b). Thus, works on magnetic nanoparticles are often focused on their cooperation with mSiO₂.

The cooperation of magnetic nanoparticles and mSiO₂ results in multifunctional nanocomposites with both magnetic for MRI and mesopores for drug loading and delivery. Kim et al. achieved discrete encapsulation of one Fe₃O₄ nanoparticle in one MSN (Kim et al., 2008), the Fe₃O₄@mSiO₂ core-shell nanoparticles with a diameter of 40–90 nm proved to be desirable T₂ MR contrast agents. Zhao et al. synthesized rattle-type hollow magnetic mesoporous spheres with a cavity created through post hydrothermal treatment (Zhao et al., 2008), and set the nanocomposite as a drug loading and delivery model. As drug delivery nanocarriers, loading capacity is an important parameter, thus the pursue for large drug loading spaces becomes a quest. Although large pore volume may increase drug loading capacity, there's yet problems such as leakages, researchers seek to fabricated yolk-shell structure with interior vacancy. Chen et al. fabricated ellipsoidal Fe₃O₄@mSiO₂ yolk-shell structure with a large cavity between the functional magnetic core and mesoporous shell (Chen et al., 2010b). In their work, SiO₂ and mSiO₂ were successively coated on the magnetic core, then the dense SiO₂ layer was selectively etched, resulting in the formation of yolk-shell structure. The yolk-shell structured nanocomposite showed an excellent biocompatibility toward all kinds of cells. While the magnetic core served as an in-vivo monitor during the therapy as T₂ contrast agent, the vacancy created proved to be an ideal drug loader with high DOX loading capacity. Such selective-etching methodology for creating controllable vacancy has been adopted by many other groups, utilizing the structure on various kinds of inorganic nanocrystals and expanding to applications even beyond drug delivery (Chen et al., 2010a; Zhu et al., 2010; Liu et al., 2011a; Wang et al., 2011).

Apart from magnetic resonance bio-imaging, another advantage of magnetic nanoparticles is the external magnetic field enhanced target drug delivery, a targeting method unnecessary for modifying of targeting molecules such as antibody (Kapse-Mistry et al., 2014). Liu et al. performed magnetic field directed cellular uptake experiment of Fe₃O₄@mSiO₂ nanoparticles and achieved doubled uptake efficiency on A549 cancer cells (Liu et al., 2012). Xiong et al. fabricated Fe₃O₄@mSiO₂ with large 15-nm radial mesopores for the delivery of siRNA (Xiong et al., 2016), a further layer of pH responsive tannic acid was deposed onto the nanoparticle to protect siRNA from degradation. Such design enabled magnetically induced high delivery efficiency and pH responsive release of siRNA. The enhanced gene delivery through magnetic vectors is given the name “magnetofection.” Much research has been conducted in the field, and showed promising future in in-vivo applications (Scherer et al., 2002; Mykhaylyk et al., 2007; Plank et al., 2011).

Current applications of magnetic nanoparticles functionalized MSNs are mostly focused on bio-imaging and targeted delivery of drug. Other functions such as detection and isolation (Song et al., 2011), magnetic hyperthermia (Wang D. W. et al., 2013; Yang et al., 2014), etc. might prefer more attention. Beside superparamagnetic nanoparticles, which at times face problems such as spin-canting, low saturation magnetization, and slow magnetic response, magnetic nanoparticles with vortex domain would also be a promising choice for bio-applications (Fan et al., 2010; Kim et al., 2010).

Fluorescence nanoparticles find their usages in almost every field of bio-applications, including diagnosis, luminescence guided therapy (Lim, 2016), light triggered drug delivery, photodynamic therapy (PDT), etc. Quantum dots (QDs) and lanthanide doped upconversion nanoparticles (UCNPs) are the two most frequently used inorganic fluorescence nanoparticles (Li et al., 2013a,b; Li et al., 2014a, 2015a, 2016) However, most fluorescence nanoparticles suffer from bad aqueous dispersity due to the oil-phase solvent-thermal fabrication process, thus naturally leads to the coating of SiO₂ to prevent aggregation and to protect the inner core from quenching or harsh environment (Li et al., 2015a).

Many works focused on fluorescence bio-imaging have been done. Li et al. designed CdTe@mSiO₂ nanoparticles and realized real-time intracellular luminescence imaging of tumor cells (Li J. et al., 2014). Zhang et al. used NaYF₄;Yb;Er@mSiO₂ for cell imaging and drug delivery (Zhang et al., 2013). Lanthanide elements such as Gd³⁺, due to the complex 4f electrons, may also serve as MRI agents. Thus the same group proposed NaYF₄;Yb;Er@NaGdF₄;Yb core-shell UCNP encapsulated in mSiO₂ for fluorescence and MRI dual-model bio-imaging (Li C. et al., 2013). Comparing to fluorescence imaging only, dual-model bio-imaging provide more accurate information toward the target, avoiding problems such as misdiagnose. Beside UV-vis fluorescence, second near-infrared window fluorescent bio-imaging of lanthanide doped nanoparticles also attracted a lot of attention. Both the excitation and emission are in the biological window for such infrared radiation (NIR) excited second NIR window (NIR-II) down-conversion fluorescent bio-imaging nanoparticles, allowing them to avoid many in-vivo disturbance, promoting the bio-imaging ability of the materials. For example, Wang fabricated SiO₂-Nd@SiO₂@mSiO₂ nanoparticles with down-conversion fluorescence that can withstand harsh gastrointestinal conditions, serving as a real-time drug release monitor (Wang et al., 2017).

Stimuli-responsivity is of great significance in drug delivery, light triggered systems offer stimuli control both in time and location, thus would naturally attract attention. While various works have been done on controlled drug delivery under UV light, the near NIR triggering ability of UCNPs tend to be more valuable, since NIR radiation have better penetration and less damage toward tissues. Liu et al. contributed to the foundational work in the field (Liu et al., 2013). The group prepared NaYF₄:Tm,Yb@NaYF₄ core–shell nanoparticles, which emit UV/blue emission under NIR, and subsequently coated the UCNPs with mSiO₂. “Photomechanical” azobenzene groups (azo) were then installed into the mesopores to act as UV/blue responsive “stirrer” to send out loaded guest molecules in the mSiO₂. Such delicate design allows almost precise control of the amount of released DOX by varying the intensity or time of NIR light irradiation. This basic concepts were adopted by many other works that followed (Luo et al., 2013; Li W. et al., 2014; Min et al., 2014; Song and Yang, 2015).

Besides chemotherapy, photodynamic therapy (PDT) is another route for light-triggered therapeutic processes. PDT involves activation of photosensitizer (PS) with light to produce single oxygen, killing the tumor cells (Cui et al., 2013; Wang C. et al., 2013). Qian et al. incorporated zinc (II) phthalocyanine (ZnPc) into NaYF₄;Yb/Er@mSiO₂, using the NIR excited Er³⁺ green emission to active the photosensitizer to release reactive singlet oxygen for tumor therapy (Qian et al., 2009).

Loading of multiple guests and multifunctional fluorescence inorganic nanocrystals raise the possibility of designing functional MSNs with multiple controllable diagnosis and therapy process, thus the previously mentioned light triggering functionalities could be gathered altogether in one single nanoparticle. Combined therapy and diagnostic, theranostic process, allows more precise treatment toward disease. In order to realize imaging-guided combined PDT and chemotherapy, Li et al. fabricated six-layered UCNPs with orthogonal excitations-emissions upconversion luminescence and further combined them with mSiO₂ to form the yolk-shell structured UCNPs@mSiO₂ nanocomposites (Figures 1C,D). In this nanocomposite, the 1,050-nm NIR down-conversion luminescence (DCL) under low power density 796-nm excitation is used as a bioimaging signal. UV/blue emission under 980-nm excitation could be used to trigger the release of the chemotherapy drug in the hollow through introduction of azo groups. Independently, the PDT can also be realized under the stimulus of green emission excited by 796 nm (Li et al., 2016). Such design allowed the control of multiple therapy process through different excitation signal.

Many inorganic materials such as Au, CuS, graphene oxide, etc. can absorb and convert NIR light into thermal energy, causing localized heating which may effectively kill tumor cells. The therapy process of light triggered thermal effect is called photothermal therapy (PTT). Beside directly killing tumor cells through heat generation, the thermal energy can be used as a switch for drug delivery, either by heat-induced molecular movements or combining with thermal sensitive gatekeeper polymers. Yet, similar to other inorganic nanocrystals, this class of nanoparticles also suffer from low drug-loading capacity and easy aggregation.

In order to make up the above mentioned deficiencies, researchers try to combine photothermal materials with the mSiO₂. Yang et al. synthesized cubic Ag@mSiO₂ yolk shell structure, and then achieved Au nanocage@mSiO₂ through galvanic replacement. A layer of thermal responsive polymer poly(nisopropylacrylamide) (PNIPAM) was coated outside the MSNs as a gatekeeper. Upon NIR radiation, heat generated by Au nanocages eventually lead to the collapse of PNIPAM shell, releasing the loaded DOX inside, realizing controlled PTT and chemotherapy (Yang et al., 2013). Such design prevented the leakage of drugs during in-vivo blood cycles, greatly raising the delivery efficiency. Zhang et al. coated mSiO₂ with Au nanorods to used them as multifunctional theranostic platforms to serve as all-in-one two-photon imaging (TPI) agents, hyperthermia agent and drug carrier (Figures 1E,F; Zhang Z. J. et al., 2012). Other materials beside Au also possess photothermal ability, Chen et al. used CuS@mSiO₂ as theranostic nanomedicine and ablated mice's 4T1 tumor after laser excitation with none regrowth over 2 months (Chen et al., 2015).

Most recently, combined therapy with dual-drugs of different therapeutic effects showed excellent performance in treatment of diseases, especially in drug-resistant cancer treatments (Zhang et al., 2010; Zhang F. et al., 2012; Fan et al., 2013; Liu et al., 2015). One of the main challenges in realizing the best therapeutic effects is that the species and doses of drugs should be optimized at different clinical manifestations and periods in the treatment. However, simple drug delivery systems cannot fulfill the requirements of this combined therapy, because the widely used carriers such as MSNs (Deng et al., 2008), hollow structured nanoparticles (Zhang et al., 2016), yolk-shell nanoparticles (Zhu et al., 2010), etc. normally possess symmetrical geometry with limited single storage space available for loading of multiple drug species. When dual-drugs are loaded in a single storage space, release of each drug cannot be controlled independently. Therefore, developing asymmetric multi-compartment carriers with independent storage spaces for loading multiple drugs is critically desired. Nanoparticles with asymmetric nanostructures on geometry, chemical composition, surface property, and functionality, etc. have aroused extensive concern for their unique characteristics and potential applications. Compared with the conventional symmetric hybrid materials, the structural asymmetry is ideally suited for multiple-component conjugations, loading, or designing of smart delivery system on single-particle level. The nanocomposites with geometrical asymmetry determines that the function of each component can work independently without interaction with each other. These characteristics of the asymmetric nanoparticles render them truly “multifunctional entities.”

Most recently, Li et al. first developed a novel anisotropic growth strategy for the fabrication of Janus structured dual-compartment multi-functional UCNP@SiO₂@mSiO₂&PMO (PMO = periodic mesoporous organosilica) nanocomposites. Start with the core@shell@shell structured UCNP@SiO₂@mSiO₂ nanospheres, the PMO single-crystal nanocubes can anisotropic island nucleation and growth on the side of the initial nanospheres to the unique Janus morphology (Figures 2A–C; Li et al., 2014b). The obtained nanocomposites are asymmetric not only in morphology, but also in pore size and hydrophobicity/hydrophilicity, which is much important for the multiple guests co-delivery. The distinct chemical properties of the silica sources and different mesostructures of the compartments are two key factors for the formation of the asymmetric nanocomposites. According to the specific designing of the switch at the entrance of the mesopores, the dual-compartment Janus mesoporous SiO₂ nanocomposites are used in the dual-drugs co-loading and controllable releasing for high efficiency cancer cell killing. This synthetic strategy can be used in the fabrication of the asymmetry single-hole nanorattles for the co-delivery of dual guests with a great discrepancy in size (Figures 2D–F; Li et al., 2015b). Beside the anisotropic growth of cubic mesostructure, the same group also extended this strategy to the fabrication of 1D asymmetric di- and tri-block mesoporous nanocomposites with ordered hexagonal mesostructures (Figure 2G). Due to the 1D mesopore channels and the asymmetric in the function, the Au nanorod functionalized di-block Au-NR@SiO₂&EPMO (EPMO = ethane bridged periodic mesoporous organosilica) nanorods exhibit superior controllable releasing of drug molecules triggered by near-infrared light (Li et al., 2017).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.