Restructuring the Interface of Silk-Polycaprolactone Biocomposites Using Rigid-Flexible Agents.

Natural fiber-reinforced biocomposites with excellent mechanical and biological properties have attractive prospects for internal medical devices. However, poor interfacial adhesion between natural silk fiber and the polymer matrix has been a disturbing issue for such applications. Herein, rigid-flexible agents, such as polydopamine (PDA) and epoxy soybean oil (ESO), were introduced to enhance the interfacial adhesion between Antheraea pernyi (Ap) silk and a common medical polymer, polycaprolactone (PCL). We compared two strategies of depositing PDA first (Ap-PDA-ESO) and grafting ESO first (Ap-ESO-PDA). The rigid-flexible interfacial agents introduced multiple molecular interactions at the silk-PCL interface. The "Ap-PDA-ESO" strategy exhibited a greater enhancement in interfacial adhesion, and interfacial toughening mechanisms were proposed. This work sheds light on engineering strong and tough silk fiber-based biocomposites for biomedical applications.

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

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.

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

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.

Molecular Interactions and Toughening Mechanisms in Silk Fibroin-Epoxy Resin Blend Films.

Natural silkworm silks have been applied to reinforce epoxy resin to achieve sub-ambient and impact toughness in the composite. However, the molecular interactions at the silk fiber-matrix interface of the composite are poorly understood. In this work, silk fibroin extracted from Bombyx mori silk is blended with an epoxy resin polymer system to study the molecular interactions between silk fibroin, epoxy compounds, and hardeners. The effects of chemical crosslinks between epoxy groups and hardeners or silk fibroin, as well as physical crosslinks in the ß-sheet structure of silk fibroin, were discussed on the thermal stability, glass transition behavior, and mechanical properties of the blend films. A relationship between the crosslinking structure and mechanical properties for the films is proposed to enlighten on the toughening mechanisms. The findings would provide insights into forming strong and tough silk fibroin material as well as understanding the interface interactions of silk-epoxy composites.

Highly Stretchable and Tough Physical Silk Fibroin-Based Double Network Hydrogels.

Regenerated silk fibroin (RSF) is a promising biomedical material, but the poor mechanical properties of RSF hydrogels may hinder the use as structural components. Herein, an equilibrium RSF hydrogel is prepared and optimized based on the double network (DN) concept. After sufficient soaking in water and removal of small molecules, the equilibrium RSF DN hydrogels prove stable in water, strong, highly extensible, and tough with 0.26-0.44 MPa tensile strength, 500-900% elongation, and 2 MJ m-3 work of extension. The combination of high strength and extensibility is attributed to the homogeneous morphology and the hydrophobic interactions and hydrogen bonding between the two networks. The strategy in this work overcomes the previous issue of swelling and eventual fracture of as-prepared RSF/SDS DN hydrogels in water. In addition, such mechanically superior RSF DN hydrogels also display low cytotoxicity. It concludes that the elastic and tough RSF DN hydrogels could be engineered by introducing widely used polymer networks, and the hydrogels from inexpensive, environmentally friendly, and biocompatible silk fibroin may hold great potential in biomedical applications.

[Physical, chemical, and biological property of silk reinforced polycaprolactone composites for bone tissue engineering].

Objective: To develop a biodegradable implantable bone material with compatible mechanics with the bone tissue, providing a new biomaterial for clinical bone repair and regeneration. Methods: Silk reinforced polycaprolactone composites (SPC) containing 20%, 40%, and 60% silk were prepared by layer-by-layer assembly and hot-pressing technology. Macroscopic morphology was observed and microstructure were observed by scanning electron microscopy, compressive mechanical properties were detected by compression test, surface wettability was detected by surface contact angle test, degradation of materials was observed after soaking in PBS for 180 days, and proliferation of MC3T3-E1 cells was detected by cell counting kit 8 assay. Six Sprague Dawley rats were subcutaneously implanted with polycaprolactone (PCL) and 20%-SPC, respectively. Masson staining was used to analyze the in vivo degradation behavior and vascularization effect within 180 days. Results: The pore defects of the three SPC sections were relatively few. In the range of 20% to 60%, as the silk content increased and the PCL content decreased, the interlayer spacing of silk fabric decreased, and the fibers almost covered the entire cross-section. The compressive modulus and compressive strength of SPC showed an increasing trend, and the compressive modulus of 60%-SPC was slightly lower than that of 40%-SPC. There were significant differences in compressive modulus and compressive strength between the materials ( P<0.05). In vitro simulated fluid degradation experiments showed that the mass loss of the three types of SPC after 180 days of degradation was within 5%, with the highest mass loss observed in 60%-SPC. The differences in mass loss between the materials were significant ( P<0.05). As the silk content increased, the static water contact angle of each material gradually decreased, and all could promote the proliferation of MC3T3-E1 cells. The subcutaneous degradation experiment in rats showed that 20%-SPC began to degrade at 30 days after implantation, and material degradation and vascularization were significant at 180 days, which was in sharp contrast to PCL. Conclusion: SPC has the mechanical and hydrophilic properties that are compatible with bone tissue. It maintains its mechanical strength for a long time in a simulated body fluid environment in vitro, and achieves dynamic synchronization of material degradation, tissue regeneration, and vascularization through the body's immune regulation mechanism in vivo. It is expected to provide a new type of implant material for clinical bone repair.

Optimized RNA interference therapeutics combined with interleukin-2 mRNA for treating hepatitis B virus infection.

This study aimed to develop a pan-genotypic and multifunctional small interfering RNA (siRNA) against hepatitis B virus (HBV) with an efficient delivery system for treating chronic hepatitis B (CHB), and explore combined RNA interference (RNAi) and immune modulatory modalities for better viral control. Twenty synthetic siRNAs targeting consensus motifs distributed across the whole HBV genome were designed and evaluated. The lipid nanoparticle (LNP) formulation was optimized by adopting HO-PEG2000-DMG lipid and modifying the molar ratio of traditional polyethylene glycol (PEG) lipid in LNP prescriptions. The efficacy and safety of this formulation in delivering siHBV (tLNP/siHBV) along with the mouse IL-2 (mIL-2) mRNA (tLNP/siHBVIL2) were evaluated in the rAAV-HBV1.3 mouse model. A siRNA combination (terms "siHBV") with a genotypic coverage of 98.55% was selected, chemically modified, and encapsulated within an optimized LNP (tLNP) of high efficacy and security to fabricate a therapeutic formulation for CHB. The results revealed that tLNP/siHBV significantly reduced the expression of viral antigens and DNA (up to 3log10 reduction; vs PBS) in dose- and time-dependent manners at single-dose or multi-dose frequencies, with satisfactory safety profiles. Further studies showed that tLNP/siHBVIL2 enables additive antigenic and immune control of the virus, via introducing potent HBsAg clearance through RNAi and triggering strong HBV-specific CD4+ and CD8+ T cell responses by expressed mIL-2 protein. By adopting tLNP as nucleic acid nanocarriers, the co-delivery of siHBV and mIL-2 mRNA enables synergistic antigenic and immune control of HBV, thus offering a promising translational therapeutic strategy for treating CHB.

Mechanically robust and personalized silk fibroin-magnesium composite scaffolds with water-responsive shape-memory for irregular bone regeneration.

The regeneration of critical-size bone defects, especially those with irregular shapes, remains a clinical challenge. Various biomaterials have been developed to enhance bone regeneration, but the limitations on the shape-adaptive capacity, the complexity of clinical operation, and the unsatisfied osteogenic bioactivity have greatly restricted their clinical application. In this work, we construct a mechanically robust, tailorable and water-responsive shape-memory silk fibroin/magnesium (SF/MgO) composite scaffold, which is able to quickly match irregular defects by simple trimming, thus leading to good interface integration. We demonstrate that the SF/MgO scaffold exhibits excellent mechanical stability and structure retention during the degradative process with the potential for supporting ability in defective areas. This scaffold further promotes the proliferation, adhesion and migration of osteoblasts and the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. With suitable MgO content, the scaffold exhibits good histocompatibility, low foreign-body reactions (FBRs), significant ectopic mineralisation and angiogenesis. Skull defect experiments on male rats demonstrate that the cell-free SF/MgO scaffold markedly enhances bone regeneration of cranial defects. Taken together, the mechanically robust, personalised and bioactive scaffold with water-responsive shape-memory may be a promising biomaterial for clinical-size and irregular bone defect regeneration.

A Cell-Free Silk Fibroin Biomaterial Strategy Promotes In Situ Cartilage Regeneration Via Programmed Releases of Bioactive Molecules.

In situ tissue regeneration using cell-free biofunctional scaffolds has been extensively studied as a promising alternative strategy to promote cartilage repair. In this study, a cartilage-biomimetic silk fibroin (SF)-based scaffold with controlled sequential release of two bioactive molecules is developed. Transforming growth factor-ß1 (TGF-ß1) is initially loaded onto the SF scaffolds by physical absorption, which are then successively functionalized with bone marrow mesenchymal stem cells (BMSCs)-specific-affinity peptide (E7) via gradient degradation coating of Silk fibroin Methacryloyl (SilMA)/Hyaluronic acid Methacryloyl (HAMA). Such SF-based scaffolds exhibit excellent structural stability and catilage-like mechanical properties, thus providing a desirable 3D microenvironment for cartilage reconstruction. Furthermore, rapid initial release of E7 during the first few days, followed by slow and sustained release of TGF-ß1 for as long as few weeks, synergistically induced the recruitment of BMSCs and chondrogenic differentiation of them in vitro. Finally, in vivo studies indicate that the implantation of the biofunctional scaffold markedly promote in situ cartilage regeneration in a rabbit cartilage defect model. It is believed that this cartilage-biomimetic biofunctional SF-based scaffold with sequential controlled release of E7 and TGF-ß1 may have a promising potential for improved cartilage tissue engineering.

Understanding the Interfacial Adhesion between Natural Silk and Polycaprolactone for Fabrication of Continuous Silk Biocomposites.

The poor interfacial adhesion between silk fiber and polyester species remains a critical problem for the optimal mechanical performance of silk-reinforced polyester composites. Here, we investigated in quantitative terms the interfacial properties between natural silk fibers and polycaprolactone (PCL) at nano-, micro-, and macroscales and fabricated continuous silk-PCL composite filaments by melt extrusion and drawing processing of PCL melt at 100, 120, and 140 °C. Bombyx mori (Bm) silk, Antheraea pernyi (Ap) silk, and polyamide6 (PA6) fiber were compared to the composite with PCL. The Ap silk exhibited the highest surface energy, the best wettability, and the largest interfacial shear strength (IFSS) with PCL. The silk-PCL composite from the 120 °C melt processing displayed the highest tensile modulus, implying an optimal temperature for interfacial adhesion. The Raman imaging technique revealed in detail the nature of the physical fusion of the interface phase in these silk- and polyamide-reinforced PCL composites. This work is intended to lay a foundation for the design and processing of robust composites from continuous silk fibers and bioresorbable polyesters for potential structural biomaterials.

Processing, mechanical properties and bio-applications of silk fibroin-based high-strength hydrogels.

Hydrogels are an attractive class of materials that possess similar structural and functional characteristics to wet biological tissues and demonstrate a diversity of applications in biomedical engineering. Silk fibroin (SF) is a unique natural polymer due to its fibrous protein nature, versatile formats, biocompatibility, tunable biodegradation and is thus a good hydrogel candidate for bio-applications. Compared to synthetic polymer hydrogels, poor mechanical performance is still a fatal drawback that hinders the application of SF hydrogels as structural materials. Researchers have attempted to develop strategies to construct silk fibroin-based high-strength hydrogels (SF-HSHs). Herein, we firstly provide an overview of the approaches of processing SF-HSHs with a focus on the physical/non-covalent crosslinking mechanisms. The examples of SF-HSHs are discussed in detail under four categories, including physical-crosslinked, dual-crosslinked, double network and composite hydrogels respectively. A brief section follows to elucidate on the gelation mechanisms of SF-HSHs before a description of the utility of SF-HSHs in biomedicine and devices is presented. Finally, the potential challenges and future development of SF-HSHs are briefly discussed. This review aims to enhance our understanding of the structure-mechanical property-function relationships of soft materials made from natural polymers and guide future research of silk fibroin-based hydrogels for biomedical applications. STATEMENT OF SIGNIFICANCE: Silk fibroin (SF) extracted from silk fibres is increasingly applied in the biomedical field, and SF hydrogel has been an emerging area for frontier bio-research. Since SF biopolymer has an intrinsic tendency to form regular ß-sheet stacks, it can be processed into purely physically crosslinked hydrogels, thus avoiding the use of chemical crosslinkers. Nevertheless, akin to other natural polymers, lab-produced SF is variable (i.e. the molecular weight and distribution), and the gelation of SF hydrogel is challenging to control. In addition, hydrogels made from SF are usually weak and brittle, which hinders the wide use of this biofriendly and biodegradable hydrogel. Recently, there is a pressing need for high strength hydrogels from natural polymers for biomedical applications, and SF is proposed as a strong candidate. Therefore, we have studied the literature in the past 10 years and would like to focus on the gelation mechanism and mechanical strength of SF hydrogels for the review.

Systematic review of intervertebral disc repair: a bibliometric analysis of the 100 most-cited articles.

STUDY DESIGN: A bibliometric review of the literature. OBJECTIVE: To identify the most frequently cited articles relating to the repair of intervertebral disc (IVD) and to summarize the key points and findings of these highly cited works, to quantify their impact on the developments of the disc disease treatment. IVD repair is an ever-growing and multi-disciplinary innovating treatment method for disc diseases. There are numerous literatures and related studies about it, promoting the development of the field. A comprehensive review and analysis of the most influential articles can help clarify the most effective strategy of IVD repair, and discover the promising directions for future research. METHODS: The Thomson Reuters Web of Knowledge was searched for citations of all literatures relevant to IVD repair. The number of citations, key points, categories, authorships, years, journals, countries, and institutions of publications were analyzed. RESULTS: The most highly cited articles in IVD Repair were published over 30 years, between 1991 and 2017. Most works (No. 41) were published between 2005 and 2009. The most-cited article was Sakai's 2003 article which described the possibility of combining MSC and gel to repair IVD. The three most popular categories involved were Orthopedics [44], Clinical Neurology [34], Engineering, and Biomedical [24]. The three most common topics were regenerative medicine and the progenitor cells [33], biomaterials and cellular scaffolds [29], application of growth factors [25]. Author Masuda and the partners have 4 articles in the top 100 list. The Rush University has 12 articles in the top 100 list. CONCLUSION: This report identifies the top 100 articles in IVD repair and acknowledges those individuals who have contributed the most to the study of the IVD repair and the body of knowledge used to the repair strategy making. It allows insight into the trends of this innovative and interdisciplinary subspecialty of spine surgery.

Interrogating preclinical study of liposomes: The effect of mouse strain reexamined.

Mice are arguably the most important tool in the preclinical evaluation of liposomes; however, the effects of inter-strain physiological variabilities on in vivo performance of liposomes have been seriously overlooked. The present study validated that plasma proteins (PPs) and the capability of mononuclear phagocyte system (MPS) (typically expressed by phagocytosis rate, K) were mice strain-dependent. Physiological variabilities in PPs and the phagocytosis rate jointly contributed to the inter-strain inconsistency of pharmacokinetic (PK) profiles of liposomes. For the PPs sensitive liposomes (such as plain PEGylated liposomes and folic acid functionalized PEGylated liposomes), inter-strain variabilities in PK profiles could be calibrated using the corrected phagocytic rate (KC = K×(c × Ig)/(alb×apo)), where c, Ig, alb and apo were respective the total content of complement proteins, immunoglobulins, albumin and apolipoproteins. While for the PPs insensitive liposomes (e.g., cRGD functionalized liposomes), phagocytic rate could be directly used to calibrate inter-strain difference of liposome PK profiles. Our data also warn that the reciprocal interaction between payloads and organisms would be much more complicated than that between liposomes and organisms, thus independent investigation should be conducted for each individual therapeutic agent.

Preparation of Cholera Toxin Subunit B Functionalized Nanoparticles for Targeted Therapy of Glioblastoma.

Cholera toxin subunit B (CTB) is the nontoxic moiety of cholera toxin. It can target the glycosphingolipid GM1 expressed in the blood-brain barrier (BBB), neovasculature, and glioblastoma cells. Thus, CTB has been utilized as a multifunctional molecule for targeted therapy of glioblastoma. Here, we describe a detailed method for preparation of CTB functionalized paclitaxel (PTX)-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles. This unique modification can guide nanoparticles across the BBB and target glioblastoma cells. The characterization of nanoparticles such as size, zeta potential, morphology, drug loading, and encapsulation efficiency is shown in this chapter.

Natural IgM dominates in vivo performance of liposomes.

Prevalent deposition of plasma proteins on nano-surface alters the synthetic identity of liposomes in blood circulation. The key plasma protein(s) that can dominate in vivo fate of liposomes are of central importance for preclinical design and precise medication of liposome-based therapeutics. Herein, natural IgM, but not IgG, is identified to ubiquitously absorb on liposomal surface and takes the lead in complement activation of different species. The absorbed natural IgM, which negatively correlates with the in vivo performance of liposomes, becomes a potential indicator to guide the de novo design and optimization of liposomes. More importantly, the varying natural IgM levels in cancer patients may be one of the causal factors for clinical differences in response to liposome-based therapeutics. Clinical monitoring of the natural IgM level and its binding with liposomes becomes crucial to optimize the therapeutic regimen prior to the application of liposome-based therapeutics.

Controlled Cryogelation and Catalytic Cross-Linking Yields Highly Elastic and Robust Silk Fibroin Scaffolds.

Silk biomaterials with tunable mechanical properties and biological properties are of special importance for tissue engineering. Here, we fabricated silk fibroin (SF, from Bombyx mori silk) scaffolds from cryogelation under controlled temperature and catalytic cross-linking conditions. Structurally, the cryogelled scaffolds demonstrated a greater ß-sheet content but significantly smaller ß-sheet domains compared to that without chemical cross-linking and catalyst. Mechanically, the cryogelled scaffolds were softer and highly elastic under tension and compression. The 120% tensile elongation and >85% recoverable compressive strain were among the best properties reported for SF scaffolds. Cyclic compression tests proved the robustness of such scaffolds to resist fatigue. The mechanical properties, as well as the degradation rate of the scaffolds, can be fine-tuned by varying the concentrations of the catalyst and the cross-linker. For biological responses, in vitro rat bone mesenchymal stem cell (rBMSC) culture studies demonstrated that cryogelled SF scaffolds supported better cell attachment and proliferation than the routine freeze-thawed scaffolds. The in vivo subcutaneous implantation results showed excellent histocompatibility and tissue ingrowth for the cryogelled SF scaffolds. This straightforward approach of enhanced elasticity of SF scaffolds and fine-tunability in mechanical performances, suggests a promising strategy to develop novel SF biomaterials for soft tissue engineering and regenerative medicine.

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

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.

Optically robust, highly permeable and elastic protein films that support dual cornea cell types.

Damaged corneas can lead to blindness. Due to the worldwide shortage of donor corneas there is a tremendous unmet demand for a robust corneal replacement that supports growth of the major corneal cell types. Commercial artificial corneas comprise plastic polymers that do not adequately support diverse cell growth. We present a new class of protein elastomer-dominated synthetic corneas with attractive performance that intimately couple biologically active tropoelastin to mechanically robust and durable protein silk. Fabricated films substantially replicate the natural cornea physically and by interacting with both key cells types used in cornea repair. Performance encompasses optical clarity at high transmittance, compatible refractive index, substantial glucose permeability, compliant mechanical properties, and support of both growth and function of corneal epithelial and endothelial cells.

Brain-targeted drug delivery by manipulating protein corona functions.

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 Aß1-42 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.

Enhanced immunocompatibility of ligand-targeted liposomes by attenuating natural IgM absorption.

Targeting ligands are anticipated to facilitate the precise delivery of therapeutic agents to diseased tissues; however, they may also severely affect the interaction of nanocarriers with plasma proteins. Here, we study the immunocompatibility of brain-targeted liposomes, which inversely correlates with absorbed natural IgM. Modification of long, stable positively charged peptide ligands on liposomes is inclined to absorb natural IgM, leading to rapid clearance and enhanced immunogenicity. Small peptidomimetic D8 developed by computer-aided peptide design exhibits improved immunocompatibility by attenuating natural IgM absorption. The present study highlights the effects of peptide ligands on the formed protein corona and in vivo fate of liposomes. Stable positively charged peptide ligands play double-edged roles in targeted delivery, preserving in vivo bioactivities for binding receptors and long-term unfavorable interactions with the innate immune system. The development of D8 provides insights into how to rationally design immunocompatible drug delivery systems by modulating the protein corona composition.