"Carrier-drug" layer-by-layer hybrid assembly of biocompatible polydopamine nanoparticles to amplify photo-chemotherapy.

Polydopamine (PDA) is capable of wide drug delivery for biomedical applications by virtue of an adjustable polymerization process, including surface coating and conjugation. Inspired by the polymerization of dopamine, we introduce a layer-by-layer hybrid co-assembly strategy for the incorporation of doxorubicin (DOX) and dopamine to form PDA "carrier-drug" hybrid assembly. The "carrier-drug" hybrid assembly relies on the π-π stacking interaction between the drug (DOX) and carrier (PDA), and such the stacked-layer structure enables PDA nanoparticles with a superior drug loading of 58%, which is about 1.7-fold higher than that of the DOX surface coating (∼35%). To further improve blood circulation stability and enhance tumor penetration, we herein propose the conjugation of native apolipoprotein A-I (apoA-I) with tumor-homing cyclic peptide iRGD for PDA surface modification. The "carrier-drug" hybrid assembly can respond to triple stimuli of the acidic pH, concentrated reactive oxygen species (ROS), and near-infrared (NIR) light irradiation for realizing site-specific and on-demand drug release. In chemo-photothermal synergy therapy, the "carrier-drug" hybrid assembly performs efficient tumor penetration and accumulation, dramatically suppressing tumor growth and metastasis in a 4T1 orthotopic tumor-bearing mice model at a safe level. Collectively, our findings share new insights into the design of "carrier-drug" hybrid assembly for enhanced chemo-photothermal oncotherapy.

Lipoprotein-Inspired Nanoscavenger for the Three-Pronged Modulation of Microglia-Derived Neuroinflammation in Alzheimer's Disease Therapy.

The inflammatory dysfunction of microglia from excess amyloid-ß peptide (Aß) disposal is an overlooked but pathogenic event in Alzheimer's disease (AD). Here, we exploit a native high-density lipoprotein (HDL)-inspired nanoscavenger (pHDL/Cur-siBACE1) that combines the trinity of phosphatidic acid-functionalized HDL (pHDL), curcumin (Cur), and ß-site APP cleavage enzyme 1 targeted siRNA (siBACE1) to modulate microglial dysfunction. By mimicking the natural lipoprotein transport route, pHDL can penetrate the blood-brain barrier and sequentially target Aß plaque, where Aß catabolism is accelerated without microglial dysfunction. The benefit results are from a three-pronged modulation strategy, including promoted Aß clearance with an antibody-like Aß binding affinity, normalized microglial dysfunction by blocking the NF-κB pathway, and reduced Aß production by gene silence (44%). After treatment, the memory deficit and neuroinflammation of APPswe/PSEN 1dE9 mice are reversed. Collectively, this study highlights the double-edged sword role of microglia and provides a promising tactic for modulating microglial dysfunction in AD treatment.

Lipoprotein-inspired penetrating nanoparticles for deep tumor-targeted shuttling of indocyanine green and enhanced photo-theranostics.

Since conventional chemotherapy has a variety of deficiencies and severe side effects, phototherapy has recently aroused great interest worldwide owing to its great potential towards theranostic applications. However, the physiological barrier of tumors hindered the penetration of therapeutic and imaging agents into the center of tumors. In this study, a novel biomimetic nanoplatform inspired by high-density lipoproteins (HDLs) was designed with deep tumor penetrating ability and integrated the clinical imaging agent indocyanine green (ICG) for synergistic phototherapy. Specifically, the HDL-protein was conjugated with the tumor-homing iRGD peptide via an applicable cross-linker to obtain a similar α helix structure, which served as an organizing scaffold for maintaining lipid nanoparticle structure. Our study illustrated that the mimicking nanoparticles shared nanosized diameters and superior biostability compared with free ICG. Once irradiated by NIR light, the encapsulated ICG could produce heat in localized ranges for photothermal therapy (PTT) and sufficient reactive oxygen species (ROS) for photodynamic therapy (PDT). Moreover, the fluorescence of ICG excited by NIR light effectively assisted in diagnosis. After intravenous injection, HDL mimicking nanoparticles could penetrate into deep tumors to realize enhanced phototherapy (PTT and PDT) under NIR laser irradiation. This biomimetic drug delivery system could open an avenue for the production of tailored theranostic nanoplatforms for personalized medicine in the near future.

Deep Tumor Penetrating Bioparticulates Inspired Burst Intracellular Drug Release for Precision Chemo-Phototherapy.

The relevance of personalized medicine has inspired research for individually concerted diagnosis and therapy. Numerous efforts are devoted to designing drug particulates with capabilities of tumor penetrating and subcellular trafficking to concurrently discharge theranostics in response to multistimulations. In this study, a bioinspired particulate, formulated with whole components of native high-density lipoproteins (HDLs) and decorated with the tumor-penetrating peptide iRGD, is proposed to promote tumor penetration of HDLs (pHDLs) together with payloads. Specifically, paclitaxel (PTX), and the NIR fluorescent probe indocyanine green (ICG) are integrated into pHDLs (pHDL/PTX-ICG) for synergetic chemo-phototherapy. Inspired by lipoproteins, pHDLs are not only restored from naturally occurring materials but also possessed artificially endowed functions, leading to an enhanced cellular uptake, higher accumulation, and deep penetration into tumors without causing appreciable adverse effects, compared to reconstituted HDLs or lipid-based nanoparticles. After intravenous administration, pHDL/PTX-ICG performs a burst of intracellular drug release and imaging-guided precision chemo-phototherapy upon NIR irradiation that completely eradicates xenograft tumors. Neither recurrence nor significant toxicity is observed due to maneuvered regional photodynamic and photothermal therapy. Taken together, pHDL/PTX-ICG is proven to be a promising platform to achieve deep tumor penetration and imaging-guided chemo-phototherapy.