New achievements in the realm of nanoscience and innovative techniques of nanomedicine have moved micro/nanoparticles (MNPs) to the point of becoming actually useful for practical applications in the near future. Various differences between the extracellular and intracellular environments of cancerous and normal cells and the particular characteristics of tumors such as physicochemical properties, neovasculature, elasticity, surface electrical charge, and pH have motivated the design and fabrication of inventive “smart” MNPs for stimulus-responsive controlled drug release. These novel MNPs can be tailored to be responsive to pH variations, redox potential, enzymatic activation, thermal gradients, magnetic fields, light, and ultrasound (US), or can even be responsive to dual or multi-combinations of different stimuli. This unparalleled capability has increased their importance as site-specific controlled drug delivery systems (DDSs) and has encouraged their rapid development in recent years. An in-depth understanding of the underlying mechanisms of these DDS approaches is expected to further contribute to this groundbreaking field of nanomedicine. Smart nanocarriers in the form of MNPs that can be triggered by internal or external stimulus are summarized and discussed in the present review, including pH-sensitive peptides and polymers, redox-responsive micelles and nanogels, thermo- or magnetic-responsive nanoparticles (NPs), mechanical- or electrical-responsive MNPs, light or ultrasound-sensitive particles, and multi-responsive MNPs including dual stimuli-sensitive nanosheets of graphene. This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.

Graphene oxide nanowalls with extremely sharp edges and preferred vertical orientation were deposited on a graphite electrode by using electrophoretic deposition in an Mg(2+)-GO electrolyte. Using differential pulse voltammetry (DPV), reduced graphene nanowalls (RGNWs) were applied for the first time, in developing an ultra-high-resolution electrochemical biosensor for detection of the four bases of DNA (G, A, T, and C) by monitoring the oxidation signals of the individual nucleotide bases. The extremely enhanced electrochemical reactivity of the four free bases of DNA, single-stranded DNA, and double-stranded DNA (dsDNA) at the surface of the RGNW electrode was compared to electrochemical performances of reduced graphene nanosheet (RGNS), graphite, and glassy carbon electrodes. By increasing the number of DPVs up to 100 scans, the RGNW electrode exhibited an excellent stability with only 15% variation in the oxidation signals, while for the RGNS electrode no detectable signals relating to T and C of 0.1 μM dsDNA were observed. The linear dynamic detection range of the RGNW electrode for dsDNA was checked in the wide range of 0.1 fM to 10 mM, while for the RGNS electrode, it was from 2.0 pM to <10 mM. The lower limits of dsDNA detection of the RGNW and RGNS electrodes were estimated as 9.4 zM (∼5 dsDNA/mL) and 5.4 fM, respectively. The RGNWs were efficient in label-free detection of single nucleotide polymorphisms of 20 zM oligonucleotides (∼10 DNA/mL) having a specific sequence. Therefore, the RGNWs can effectively contribute to the development of ultra-high-sensitive electrochemical biosensors with single-DNA resolutions.

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Graphene oxide nanoplatelets (GONPs) with extremely sharp edges (lateral dimensions ∼ 20-200 nm and thicknesses <2 nm) were applied in extraction of the overexpressed guanine synthesized in the cytoplasm of leukemia cells. The blood serums containing the extracted guanine were used in differential pulse voltammetry (DPV) with reduced graphene oxide nanowall (rGONW) electrodes to develop fast and ultra-sensitive electrochemical detection of leukemia cells at leukemia fractions (LFs) of ∼ 10(-11) (as the lower detection limit). The stability of the DPV signals obtained by oxidation of the extracted guanine on the rGONWs was studied after 20 cycles. Without the guanine extraction, the DPV peaks relating to guanine oxidation of normal and abnormal cells overlapped at LFs <10(-9), and consequently, the performance of rGONWs alone was limited at this level. As a benchmark, the DPV using glassy carbon electrodes was able to detect only LFs ∼ 10(-2). The ultra-sensitivity obtained by this combination method (guanine extraction by GONPs and then guanine oxidation by rGONWs) is five orders of magnitude better than the sensitivity of the best current technologies (e.g., specific mutations by polymerase chain reaction) which not only are expensive, but also require a few days for diagnosis.

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