A Conditionally Releasable “Do not Eat Me” CD47 Signal Facilitates Microglia‐Targeted Drug Delivery for the Treatment of Alzheimer's Disease

Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting “do not eat me” signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable “do not eat me” CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.     

Amyloid‐β Oligomer‐Targeted Gadolinium‐Based NIR/MR Dual‐Modal Theranostic Nanoprobe for Alzheimer's Disease

While the deposition of amyloid‐β (Aβ) plaques is one of the main pathological hallmarks of incurable Alzheimer's disease (AD), Aβ oligomers have been identified as a more appealing AD biomarker due to their being more pathogenic and neurotoxic. Therefore, the development of a sensitive and effective technique for oligomeric Aβ detection and imaging is beneficial for the early detection of AD, monitoring disease progression, and assessing the efficacy of potential AD drugs. Herein, the development and investigation of the first Aβ oligomer‐specific Gd³⁺‐based nanoparticles (NPs), NP@SiO₂@F‐SLOH as a multimodal near‐infrared imaging (NIRI)/T₁‐weighted magnetic resonance imaging (MRI) contrast agent for real‐time visualization of Aβ contents in an AD mouse model is reported. Remarkably, the NP@SiO₂@F‐SLOH is successfully applied for in vivo and ex vivo NIRI with high sensitivity and selectivity for Aβ oligomers and for MRI with good spatial resolution in different age groups in an AD mouse model. Furthermore, the NP probe exhibits a noticeable inhibitory effect on Aβ fibrillation and neuroprotection against Aβ‐induced toxicity indicating its desirable therapeutic potential for AD. All these results illustrate the tremendous potential of this versatile and sensitive nanomaterial as an effective theranostic MRI nanoprobe for practical use.     

Dual Bioresponsive Mesoporous Silica Nanocarrier as an “AND” Logic Gate for Targeted Drug Delivery Cancer Cells

Despite the rapid development of drug delivery vehicles that react to a specific biological environment, the complexity of triggering drug release in a particular target area remains an enduring challenge. Here, the engineering of bioresponsive polymer‐mesoporous silica nanoparticles (MSNs) with function akin to an AND logic gate is described. Polycaprolactone (esterase degradable) is immobilized into the core of MSNs while polyacrylic acid (PAA), which is pH responsive, covered the outside of the MSNs to create a PAA‐PCL‐MSNs construct. Fluorescence spectroscopy indicates that the construct releases the payload (doxorubicin, cancer drugs) in the presence of, and only in the presence of, both low pH AND esterase. Confocal microscopy and fluorescence lifetime microscopy (FLIM) demonstrate uptake of the intact construct and subsequent intracellular doxorubicin (DOX) delivery into the nucleus. Further in vitro IC₅₀ studies demonstrate the AND logic gate delivery system results in more than an eightfold efficacy against neuroblastoma (SK‐N‐BE(2)) cells in comparison with normal fibroblasts (MRC‐5). These results demonstrate the utility of MSN‐polymer construct to create an AND gate capable of selectively delivering a drug payload.     

Engineering Versatile Nanoparticles for Near‐Infrared Light‐Tunable Drug Release and Photothermal Degradation of Amyloid β

Nanomedicines that inhibit/disassemble amyloid β (Aβ) aggregates in Alzheimer's disease (AD) are highly desirable yet remain challenging. Therapeutic efficacy and systemic delivery of reported molecules and nanoparticles (NPs) are hampered by various challenges, including low biocompatibility, off‐target toxicity, and lack of specificity. Herein, a versatile NP is designed by integrating high Aβ‐binding affinity, stimuli‐responsive drug release, and photothermal degradation properties for efficient disassembly of Aβ. Near‐infrared (NIR)‐absorbing conjugated polymer PDPP3T‐O14 serves as a photothermal core while thermal‐responsive polymer 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine at the outer layer as the NIR‐stimuli gatekeeper. Curcumin, an inhibitor of Aβ aggregation, is loaded into the NP with high encapsulation efficiency. The 5‐mer β‐sheet breaker peptides LPFFD (Leu‐Pro‐Phe‐Phe‐Asp) having high binding affinity toward Aβ are further anchored onto the surface of polyethylene glycol‐lipid shell for active Aβ‐targeting. The resultant NPs exhibit good Aβ‐targeting ability and obvious photothermal dissociation effect together with Aβ aggregation‐dependent fluorescence detection capability. Upon NIR laser irradiation, entrapped curcumin can be effectively released from the unconsolidated NPs to enhance the anti‐amyloid activity. In vitro studies demonstrate that the NPs dramatically lower Aβ‐induced cytotoxicity of PC12 cells, and therefore show great potential for the application in AD treatment.