With the unprecedented progresses of biomedical nanotechnology during the past few decades, conventional drug delivery systems (DDSs) have been involved into smart DDSs with stimuli-responsive characteristics. Benefiting from the response to specific internal or external triggers, those well-defined nanoplatforms can increase the drug targeting efficacy, in the meantime, reduce side effects/toxicities of payloads, which are key factors for improving patient compliance. In academic field, variety of smart DDSs have been abundantly demonstrated for various intriguing systems, such as stimuli-responsive polymeric nanoparticles, liposomes, metals/metal oxides, and exosomes. However, these nanoplatforms are lack of standardized manufacturing method, toxicity assessment experience, and clear relevance between the pre-clinical and clinical studies, resulting in the huge difficulties to obtain regulatory and ethics approval. Therefore, such relatively complex stimulus-sensitive nano-DDSs are not currently approved for clinical use. In this review, we highlight the recent advances of smart nanoplatforms for targeting drug delivery. Furthermore, the clinical translation obstacles faced by these smart nanoplatforms have been reviewed and discussed. We also present the future directions and perspectives of stimuli-sensitive DDS in clinical applications.

As pioneering Fe₃O₄nanozymes, their explicit peroxidase (POD)-like catalytic mechanism remains elusive. Although many studies have proposed surface Fe²⁺-induced Fenton-like reactions accounting for their POD-like activity, few have focused on the internal atomic changes and their contribution to the catalytic reaction. Here we report that Fe²⁺within Fe₃O₄can transfer electrons to the surface via the Fe²⁺-O-Fe³⁺chain, regenerating the surface Fe²⁺and enabling a sustained POD-like catalytic reaction. This process usually occurs with the outward migration of excess oxidized Fe³⁺from the lattice, which is a rate-limiting step. After prolonged catalysis, Fe₃O₄nanozymes suffer the phase transformation to γ-Fe₂O₃with depletable POD-like activity. This self-depleting characteristic of nanozymes with internal atoms involved in electron transfer and ion migration is well validated on lithium iron phosphate nanoparticles. We reveal a neglected issue concerning the necessity of considering both surface and internal atoms when designing, modulating, and applying nanozymes.

Prussian blue (PB) modified γ-Fe₂O₃ magnetic nanoparticles (MNPs) featuring varying PB proportions were synthesized and characterized by TEM, FTIR, UV-vis, EDS, XRD and XPS. The magnetic properties and peroxidase-like catalytic activity of the synthesized nanoparticles were investigated. With increasing PB content, the magnetism could still maintain a high level. Peroxidase-like activity was enhanced as the PB proportion increased. Catalysis was found to follow Michaelis–Menten kinetics. The calculated kinetic parameters exhibited strong affinity with substrates and high catalytic activity, which are three orders of magnitudes larger than that for magnetite nanoparticles of similar size. Based on the high activity, an enzyme immunoassay model was established: staphylococcal protein A (SPA) was conjugated onto the surface of the nanoparticles to construct a new nanoprobe which was employed to detect IgG immobilized to 96-well plates. The results presented a linear absorbance enhancement with concentration of IgG, suggesting that PBMNPs serve as an inexpensive horseradish peroxidase (HRP) mimic enzyme with potential applications in bio-detection.