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The effective treatment of Alzheimer's disease (AD) is hindered due to the hard blood–brain barrier (BBB) penetration and non‐selective distribution of drugs in the brain. Moreover, the complicated pathological mechanism of AD involves various pathway dysfunctions that limit the effectiveness of a single therapeutic drug. Herein, a dendrigraft poly‐l‐lysines (DGL)‐based siRNA and D peptide (Dp) loaded nanoparticle is designed that could target and penetrate through the BBB, enter the brain parenchyma, and further accumulate at the AD lesion. In this system, T7 peptide, which specifically targets transferrin receptors on the BBB, is linked to DGL via acid‐cleavable long polyethylene glycol (PEG) to achieve high internalization, quick escape from endo/lysosome, and effective transcytosis. Then, the Tet1, which specifically targets diseased neurons, is modified onto DGL by short PEG. After being exposed, Tet1 could drive the nanoparticles to the AD lesion and release the drugs. As a result, the production of β amyloid plaques (Aβ) is inhibited. Neurotoxicity induced by Aβ plaques and tau proten phosphorylation (p‐tau) tangle is also alleviated, and the cognition of AD mice is significantly improved. Overall, this system programmatically targets BBB and neurons, thus, significantly enhances the intracephalic drug accumulation and AD treatment efficacy.

In tumor therapy, nanodrug delivery systems have gained momentum in the last decade. However, its efficacy remains insufficient for clinical applications. The physical properties of nanoparticles, including size, shape, and surface characteristics, can strongly affect the delivery efficacy. Ironically, research on shape function is relatively scarce, although the nanoparticle shape greatly impacts their performance; for example, nanorods with a high aspect ratio (AR) achieve greater accumulation, but their penetration is relatively weak. Hence, rather than selecting a suitable AR to balance them, the strategy of a transformable AR (i.e., transformation) is ideal in this case. Nanoparticle transformation can be achieved by either internal stimuli (such as pH and enzymes) or external stimuli (such as light) spatially and temporally with precision, thereby dramatically enhancing the efficiency of drug delivery. Thus, nanoparticle transformation is becoming a promising prospect for improving cancer treatment. In this review, first, the effect of shape on drug delivery is summarized, then, the recently transformable drug delivery systems are reviewed, and finally, the future direction of shape-transformable nanoparticles in tumor therapy is discussed.

No abstract

Alzheimer's disease (AD), as a progressive and irreversible brain disorder, remains the most universal neurodegenerative disease. No effective therapeutic methods are established yet due to the hindrance of the blood‐brain barrier (BBB) and the complex pathological condition of AD.  Therefore, a multifunctional nanocarrier (Rapa@DAK/siRNA) for AD treatment is constructed to achieve small interfering RNA of β‐site precursor protein (APP) cleaving enzyme‐1 (BACE1 siRNA) and rapamycin co‐delivery into the brain, based on Aleuria aurantia lectin (AAL) and β‐amyploid (Aβ)‐binding peptides (KLVFF) modified PEGylated dendrigraft poly‐l‐lysines (DGLs) via intranasal administration. Nasal administration provides an effective way to deliver drugs directly into the brain through the nose‐to‐brain pathway. AAL, specifically binding to L‐fucose located in the olfactory epithelium, endows Rapa@DAK/siRNA with high brain entry efficiency through intranasal administration. KLVFF peptide as an Aβ targeting ligand and aggregation inhibitor enables nanoparticles to bind with Aβ, inhibit Aβ aggregation, and reduce toxicity. Meanwhile, the release of BACE1 siRNA and rapamycin is confirmed to reduce BACE1 expression, promote autophagy, and reduce Aβ deposition. Rapa@DAK/siRNA is verified to improve the cognition of transgenic AD mice after intranasal administration. Collectively, the multifunctional nanocarrier provides an effective and potential intranasal avenue for combination therapy of AD.

Although drug delivery systems (DDS) are efficient in brain delivery, they face failure in clinical settings due to their potential toxicity to the central nervous system. Little is known about where the DDS will go after brain delivery, and no specific elimination route that shares a passage with DDS has been verified. Hence, identifying harmless DDS for brain delivery and determining their fate there would strongly contribute to their clinical translation. In this study, we investigated nonreactive gold nanoclusters, which can deliver into the brain, to determine the elimination route of DDS. Subsequently, nanoclusters in the brain were systemically tracked and were found to be critically drained by the glymphatic system from the blood vessel basement membrane to periphery circulations (77.8 ± 23.2% and 43.7 ± 23.4% contribution). Furthermore, the nanoclusters could be actively transported across the blood-brain barrier (BBB) by exosomes (30.5 ± 27.3% and 29.2 ± 7.1% contribution). In addition, microglia promoted glymphatic drainage and passage across the BBB. The simultaneous work of the glymphatic system, BBB, and microglia revealed the fate of gold nanoclusters for brain delivery and provided a basis for further brain-delivery DDS.