Protein corona presents a major obstacle to bench-to-bedside translation of targeted drug delivery systems, severely affecting targeting yields and directing unfavorable biodistribution. Corona-mediated targeting provides a new impetus for specific drug delivery by precisely manipulating interaction modes of functional plasma proteins on nano-surface. Here bio-inspired liposomes (SP-sLip) were developed by modifying liposomal surface with a short nontoxic peptide derived from Aβ1-42 that specifically interacts with the lipid-binding domain of exchangeable apolipoproteins. SP-sLip absorb plasma apolipoproteins A1, E and J, consequently exposing receptor-binding domain of apolipoproteins to achieve brain-targeted delivery. Doxorubicin loaded SP-sLip (SP-sLip/DOX) show significant enhancement of brain distribution and anti-brain cancer effect in comparison to doxorubicin loaded plain liposomes. SP-sLip preserve functions of the absorbed human plasma ApoE, and the corona-mediated targeting strategy works in SP modified PLGA nanoparticles. The present study may pave a new avenue to facilitate clinical translation of targeted drug delivery systems.

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Brain-targeted drug delivery by manipulating protein corona functions.

Photothermal therapy (PTT) combined with chemotherapy, a promising strategy for breast cancer treatment, has a high potential to control drug release, reduce multidrug resistance, and improve therapeutic efficacy. The challenge is how to realize tumor ablation in deeper tissue and NIR‐controlled drug delivery. Herein, tumor acidity and near‐infrared light (NIR) responsive folic acid (FA) functionalized polydopamine (DPA) nanoparticles (NPs) are developed for doxorubicin (DOX) and epigallocatechin‐3‐gallate (EGCG) dual delivery. With the assistance of NIR, the cellular uptake of DOX‐EGCG/DPA‐FA NPs is about three‐ to sixfold higher when compared with the free DOX group and the control group without NIR irradiation. Moreover, biodistribution study in vivo indicates that DPA‐FA NPs can enhance tumoral accumulation, penetration, retention of drugs, and display a ≈4‐ and 19‐fold higher intra‐tumoral distribution than that of the DPA NPs and free drug groups at 24 h postinjection. Furthermore, 60% of breast cancer‐bearing mice survive over 70 days in the DOX‐EGCG/DPA‐FA NPs group. Additionally, DOX‐EGCG/DPA‐FA NPs can effectively boost therapeutic efficacy by inducing significant suppression of tumor growth and angiogenesis, and enhancement of apoptosis and necrosis of breast cancer cells. Taken together, DOX‐EGCG/DPA‐FA NPs may have potential applications as a useful nanoscale vector for enhanced cancer therapy.

Tumor Acidity and Near‐Infrared Light Responsive Dual Drug Delivery Polydopamine‐Based Nanoparticles for Chemo‐Photothermal Therapy

Liposomes are a unique platform for drug delivery, and a number of liposomal formulations have already been commercialized. Doxil is a representative example, which uses PEGylated liposomes to load doxorubicin for cancer therapy. Its delivery relies on the enhanced permeability and retention (EPR) effect or passive targeting. Drug loading can be achieved using both standard liposomes and also those containing a solid core such as mesoporous silica and poly(lactide-co-glycolide) (PLGA). Developments have also been made on active targeted delivery using bioaffinity ligands such as small molecules, antibodies, peptides and aptamers. Compared to other types of nanoparticles, the surface of liposomes is fluid, allowing dynamic organization of targeting ligands to achieve optimal binding to cell surface receptors. This review article summarizes development of liposomal targeted drug delivery systems, with an emphasis on the biophysical properties of lipids. In both passive and active targeting, the effects of liposome size, charge, fluidity, rigidity, head-group chemistry and PEGylation are discussed along with recent examples. Most of the examples are focused on targeting tumors or cancer cells. Finally, a few examples of commercialized formulations are described, and some future research opportunities are discussed.

Targeted liposomal drug delivery: a nanoscience and biophysical perspective.

The protein corona hampers the transcytosis of transferrin-modified nanoparticles through blood-brain barrier and attenuates their targeting ability to brain tumor.

DNA nanotechnology has produced a wide range of self-assembled structures, offering unmatched possibilities in terms of structural design. Because of their programmable assembly and precise control of size, shape, and function, DNA particles can be used for numerous biological applications, including imaging, sensing, and drug delivery. While the biocompatibility, programmability, and ease of synthesis of nucleic acids have rapidly made them attractive building blocks, many challenges remain to be addressed before using them in biological conditions. Enzymatic hydrolysis, low cellular uptake, immune cell recognition and degradation, and unclear biodistribution profiles are yet to be solved. Rigorous methodologies are needed to study, understand, and control the fate of self-assembled DNA structures in physiological conditions. In this review, we describe the current challenges faced by the field as well as recent successes, highlighting the potential to solve biology problems or develop smart drug delivery tools. We then propose an outlook to drive the translation of DNA constructs toward preclinical design. We particularly believe that a detailed understanding of the fate of DNA nanostructures within living organisms, achieved through thorough characterization, is the next required step to reach clinical maturity.

DNA Nanostructures: Current Challenges and Opportunities for Cellular Delivery.

Folic acid (FA) has been extensively exploited to facilitate targeted delivery of nanomedicines by recognizing the folate receptor-α (FR-α) overexpressed in many human cancers. Unfortunately, none have been approved for clinical use yet. Here we reveal that FA functionalization induces heavy natural IgM absorption on the liposomal surface, depriving FA of receptor recognition and accelerating complement activation in vivo. FA functionalization does not enhance distribution of liposomes in FR-α-overexpressed tumors in comparison to plain liposomes (without FA), but leads to aggravated capture of liposomes by macrophages in the tumor, liver, and spleen. In addition, FA-functionalized polymeric nanoparticles are also vulnerable to natural IgM absorption. This work highlights the pivotal roles of natural IgM in regulating in vivo delivery of FA-functionalized nanomedicines. Due to the prevalent association of immune disorders and varying levels of immunoglobulins with cancer patients, extraordinary cautiousness is urged for clinical translation of FA-enabled targeted delivery systems.

Interrogation of Folic Acid-Functionalized Nanomedicines: The Regulatory Roles of Plasma Proteins Reexamined.

Natural IgM dominates in vivo performance of liposomes.

Peptide ligands have been exploited as versatile tools to facilitate targeted delivery of nanocarriers. However, the effects of peptide ligands on immunocompatibility and therapeutic efficacy of liposomes remain intricate. Here, a short and stable brain targeted peptide ligand D8 was modified on the surface of doxorubicin-loaded liposomes (D8-sLip/DOX), demonstrating prolonged blood circulation and lower liver distribution in comparison to the long and stable D-peptide ligand DCDX-modified doxorubicin-loaded liposomes (DCDX-sLip/DOX) by mitigating natural IgM absorption. Despite the improved pharmacokinetic profiles, D8-sLip/DOX exhibited comparable brain targeting capacity in ICR mice and antiglioblastoma efficacy to DCDX-sLip/DOX in nude mice bearing intracranial glioblastoma. However, dramatic accumulation of DCDX-sLip/DOX in liver (especially during the first 8 h after intravenous injection) resulted in pathological symptoms, including nuclei swelling, necrosis of liver cells, and inflammation. These results suggest that short peptide ligand-mediated brain-targeted drug delivery systems possessing enhanced immunocompatibility are promising to facilitate efficient brain transport with improved biosafety.

Short Peptide-Mediated Brain-Targeted Drug Delivery with Enhanced Immunocompatibility.

Nanovaccines are of increasing scrutiny due to their plasticity in size, composition, and surface properties to enhance antigenicity. However, inevitable absorption of plasma proteins affects the in vivo fate of nanovaccines by reshaping biological identity. Herein IgM was validated as a self-adjuvant by regulating antigen-presenting cells recognition of liposome-based nanovaccines. DCDX-modified liposomes with loading of ovalbumin (DCDX-sLip/OVA) heavily absorbed IgM via electrostatic interaction, demonstrating significant splenic B cells targeting. IgM absorbed on DCDX-sLip/OVA enhanced antigen uptake and presentation by both IgM-complement and IgM-FcμR pathways. DCDX-sLip/OVA induced a stronger IgG1 titer than ovalbumin-loaded plain liposomes (sLip/OVA) while maintaining a comparably high level of IgG2a titer with high biosafety, indicating that IgM absorption after DCDX modification could improve the antigenicity by enhancing the Th2-polarized immune response. The present work suggested manipulation of IgM absorption may provide a new impetus to improve in vivo performance of nanovaccines.

Self-Adjuvant Effect by Manipulating the Bionano Interface of Liposome-Based Nanovaccines.

Folic acid (FA) is one of the most widely utilized small-molecule ligands for cancer targeted drug delivery. Natural IgM was recently found to avidly absorb on the surface of FA-functionalized liposomes (FA-sLip), negatively regulating the in vivo performance by efficiently activating complement. Herein, FA-functionalized lipodiscs (FA-Disc) were constructed to successfully circumvent IgM-mediated opsonization and retained binding activity with folate receptors in vivo. The FA moiety along with the bound IgM was restricted to the highly curved rim of lipodiscs, leading to IgM incapability of presenting the membrane-bound conformation to trigger complement activation. The C1q docking, C3 binding, and C5a release were blocked and accelerated blood clearance phenomenon was mitigated of FA-Disc. FA-Disc retained folate binding activity and could effectively target folate receptor positive tumors in vivo. The present study provides a useful solution to avoid the negative regulation by IgM and achieve FA-enabled targeting by exploring disc-shaped nanocarriers.

Tianhao Ding

Papers

Interrogation of Folic Acid-Functionalized Nanomedicines: The Regulatory Roles of Plasma Proteins Reexamined.

Natural IgM dominates in vivo performance of liposomes.

Short Peptide-Mediated Brain-Targeted Drug Delivery with Enhanced Immunocompatibility.

Self-Adjuvant Effect by Manipulating the Bionano Interface of Liposome-Based Nanovaccines.

Folic Acid Enables Targeting Delivery of Lipodiscs by Circumventing IgM-Mediated Opsonization.