Chemical Synthesis and Multihybridization of Small-Sized Hollow Mesoporous Organosilica Nanoparticles Toward Advanced Theranostics.

As one of the most widely used nanomaterials, mesoporous silica nanoparticles (MSNs) have received extensive attraction due to their desirable physicochemical performances of high stability, large surface area, and tunable pore sizes. Besides, the U.S. Food and Drug Administration (FDA) has recognized that silica-based nanoparticles are generally safe for biomedical applications. However, the poor biodegradation and inert Si-O-Si framework of inorganic MSNs severely impair their diverse biomedical applications. A promising strategy to improve the physicochemical properties of MSNs is the incorporation of functional organic moieties into their framework to construct mesoporous organosilica nanoparticles (MONs), which exhibit distinct advantages over traditional inorganic MSNs, such as adjustable organosilica framework, excellent biocompatibility, stimuli-responsive biodegradability, and even improved therapeutic effects. Moreover, the emerging hollow-structured MONs (HMONs) with an internal cavity can offer a large drug loading capacity and thus become increasingly attractive and promising theranostic nanoplatforms in biomedicine. In recent years, numerous studies have delved into establishing multifunctional HMONs with sizes ranging in diameters from 50 to 200 nm for desirable biological responses. With the gradual deepening of research, small-sized HMONs with diameters below 50 nm (sub-50 nm HMONs) demonstrate unparalleled advantages in extending blood circulation time, reducing the risk of vascular occlusion, and achieving high tumor accumulation, thus leading to a growing interest in the design, development, and translation of sub-50 nm HMONs. However, the mechanism of the chemical synthesis and structural regulation of sub-50 nm HMONs is still unclear, which is detrimental to further structural hybridization and surface functionalization. In this account, we will focus on the structural design, chemical synthesis, adjustable framework hybridization, multifunctional surface modification, and versatile biomedical applications of small-sized HMONs. First, we will illustrate the chemical approaches for controllable synthesis of HMONs and the underlying mechanism of particle size regulation below 50 nm. Subsequently, the basic principles and design strategies of multihybridization of sub-50 nm HMONs based on framework hybridization, surface modulation, and in situ polymerization will be systematically discussed. Through diverse functionalization strategies, a series of sub-50 nm multihybridized HMONs-based nanotheranostics are established, and their applications in multimodal biomedical imaging and highly efficient synergistic treatment of various diseases (e.g., cancer, glaucoma, bacterial infection, etc.) will be accounted. Finally, we will summarize the current status and potential challenges of HMONs in clinic trials, as well as provide a comprehensive outlook on the future development of sub-50 nm HMONs. These innovative sub-50 nm HMONs hold the potential to introduce novel theranostic modalities for a variety of systemic disorders and to advance smart promising nanomedicine in the near future.