Pathogenic biofilms protected by extracellular polymeric substances frequently compromise the efficiency of antibacterial drugs and severely threaten human health. In this study, we designed a multi-stimuli-responsive magnetic supramolecular nanoplatform to co-deliver large and low molecular weight drugs for synergistic eradication of pathogenic biofilms. This co-delivery platform was composed of mesoporous silica nanoparticles (MSNs) with large pores (MSNLP) capped by β-cyclodextrin (β-CD)-modified polyethylenimine (PEICD) and adamantane (ADA)-decorated MSNs containing a magnetic core (MagNP@MSNA) capped by cucurbit[6]­uril (CB[6]). The host MSNs (H, MSNLP@PEICD) and the guest MSNs (G, MagNP@MSNA-CB[6]) spontaneously form coassemblies (H+G), based on the host–guest interactions between β-CD and ADA. Under the stimulus of pathogen cells together with heating by an alternating magnetic field (AMF), the supramolecular coassemblies released both the large molecular weight antimicrobial peptide melittin (MEL) and the low molecular weight antibiotic ofloxacin (OFL) with high efficiency. As compared to free drugs (MEL and OFL) or unattached MSNs (H or G), the drug-loading H+G coassemblies (H-MEL+G-OFL) exhibited much higher capacity for biofilm eradication, thoroughly removing biofilm biomass and killing the pathogenic cells, and displaying no obvious toxicity to mammalian cells. This strong antibiofilm capacity was severely decreased when the host and guest components were prevented from coassembling but administered simultaneously, revealing the critical role of the supramolecular assembly in biofilm removal. Moreover, an in vivo implantation model showed that the coassemblies eradicated the pathogenic biofilms from the implants, preventing host tissue damage and inflammation. Therefore, the co-delivering and multi-stimuli-responsive nanocarriers could overcome the anti-infection difficulties during treatment of infections because of protective biofilms.

Major objectives in nanomedicine and nanotherapy include the ability to trap therapeutic molecules inside of nano-carriers, carry therapeutics to the site of the disease with no leakage, release high local concentrations of drug, release only on demand - either autonomous or external, and kill the cancer cells or an infectious organism. This review will focus on mesoporous silica nanoparticle carriers (MSN) with a large internal pore volume suitable for carrying anticancer and antibiotic drugs, and supramolecular components that function as caps that can both trap and release the drugs on-command. Caps that are especially relevant to this review are rotaxanes and pseudorotaxanes that consist of a long chain-like molecule threaded through a cyclic molecule. Under certain conditions discussed throughout this review, the cyclic molecule can be attracted to one end of the rotaxane and in the presence of a stimulus can slide to the other end. When the thread is attached near the pore opening on MSNs, the sliding cyclic molecule can block the pore when it is near the particle or open it when it slides away. The design, synthesis and operation of supramolecular systems that act as stimuli-responsive pore capping devices that trap and release molecules for therapeutic or imaging applications are discussed. Uncapping can either be irreversible because the cap comes off, or reversible when the cyclic molecule is prevented from sliding off by a steric barrier. In the latter case the amount of cargo released (the dose) can be controlled. These nanomachines act as valves. Examples of supramolecular systems stimulated by chemical signals (pH, redox, enzymes, antibodies) or by external physical signals (light, heat, magnetism, ultrasound) are presented. Many of the systems have been studied in vitro proving that they are taken up by cancer cells and release drugs and kill the cells when stimulated. Some have been studied in mouse models; after IV injection they shrink tumors or kill intracellular pathogens after stimulation. Supramolecular constructs offer fascinating, highly controllable and biologically compatible platforms for drug delivery.

Stimuli-responsive multifunctional mesoporous silica nanoparticles (MSNs) have been studied intensively during the past decade. A large variety of mesopore capping systems have been designed, initially to show that it could be done and later for biomedical applications such as drug delivery and imaging. On-command release of cargo molecules such as drugs from the pores can be activated by a variety of stimuli. This paper focuses on three noninvasive, biologically usable external stimuli: magnetism, ultrasound, and light. We survey the variety of MSNs that have been and are being used and assess capping designs and the advantages and drawbacks of the nanoplatforms' responses to the various stimuli. We discuss important recent advances, their basic mechanisms, and their requirements for stimulation. On the basis of our survey, we identify fundamental challenges and suggest future directions for research that will unleash the full potential of these fascinating nanosystems for clinical applications.

In the presence of an alternating magnetic field (AMF), a superparamagnetic iron oxide nanoparticle (SPION) generates heat. Understanding the local heating mechanism of a SPION in suspension and in a mesoporous silica nanoparticle (MSN) will advance the design of hyperthermia-based nanotheranostics and AMF-stimulated drug delivery in biomedical applications. The AMF-induced heating of single-domain SPION can be explained by the Néel relaxation (reorientation of the magnetization) or the Brownian relaxation (motion of the particle). The latter is investigated using fluorescence depolarization based on detecting the mobility-dependent polarization anisotropy (r) of two luminescence emission bands at different wavelengths corresponded to the europium-doped luminescent SPION (EuSPION) core and the silica-based intrinsically emitting shell of the core–shell MSN. The fluorescence depolarization experiments are carried out with both the free and the silica-encapsulated SPION nanoparticles with and without application of the AMF. The r value of a EuSPION core-mesoporous silica shell in the presence of the AMF does not change, indicating that no additional rotational motion of the core–shell nanoparticles is induced by the AMF, disproving the contribution of Brownian heating and thus supporting Néel relaxation as the dominant heating mechanism.