BackgroundSecretory phosphoprotein 1 (SPP1) has been linked to tumor progression and immune regulation, but its prognostic value, impact on the tumor immune microenvironment (TIME), and drug sensitivity in HCC remain unclear.MethodsWe performed a pan-cancer analysis using TIMER and validated SPP1 upregulation in six GEO datasets (GSE45436, GSE54236, GSE121248, GSE76427, GSE64041, and GSE60502) and HPA protein data. In TCGA-LIHC, we assessed overall survival (OS) and progression-free survival (PFS) using univariate/multivariate Cox analyses, ROC analysis, and a calibrated nomogram. We identified differentially expressed genes (DEGs) and performed GO/KEGG and GSEA analyses. Immune infiltration was estimated with CIBERSORT and TIMER, and relationships with immune checkpoints were explored. Drug sensitivity was predicted with pRRophetic using GDSC data. In vitro, SPP1 was knocked down or overexpressed in HCC cell lines to evaluate effects on proliferation, migration, invasion, and apoptosis via qRT-PCR, Western blot, CCK-8, colony formation, wound healing, Transwell invasion, and TUNEL assays.ResultsSPP1 was significantly upregulated in HCC at mRNA and protein levels. High SPP1 predicted poorer OS and PFS and was associated with higher histological grade, advanced stage, and greater T stage. The nomogram showed good calibration and discrimination. DEGs and enrichment analyses implicated cytokine receptor interaction, fatty acid metabolism, and PI3K-Akt signaling; GSEA confirmed immune- and metabolism-related pathways. High SPP1 correlated with higher immune/ESTIMATE scores, increased M0/M2 macrophages and dendritic cells, reduced CD8 + T cells, and upregulation of multiple immune checkpoints. Drug-sensitivity predictions showed high-SPP1 tumors were more sensitive to several anti-cancer drugs (e.g., sorafenib), while resistance to others was suggested. Functionally, SPP1 knockdown inhibited, while overexpression promoted, proliferation, migration, and invasion; knockdown increased apoptosis.ConclusionsSPP1 acts as an oncogenic driver in HCC, associated with poor prognosis, an immunosuppressive TIME, and distinct drug-response patterns.

The high interfacial energy of nanomaterials limits their certain biomedical applications that require stealthiness to minimize non-specific interaction with biological components. While steric repulsion-based entropic stabilization—such as PEGylation—has long been the dominant strategy for designing stealth nanomaterials, its inherent softness and susceptibility to dynamic deformation and external forces often result in only moderate stealth performance. Here we report a distinct approach to achieving stealthiness by harnessing an ion-pair network, rather than maximizing steric repulsion. Using model polyion complex nanoparticles composed of equimolar charge ratios of polycations and polyanions, we demonstrate that increasing crosslinks between the constituent polyions beyond a critical threshold effectively reduces protein adsorption and macrophage uptake, enabling prolonged circulation with a half-life exceeding 100 hours. Building on this, we develop an asparaginase-loaded vesicular nanoreactor enveloped by a semi-permeable ion-pair network sheath for asparagine starvation therapy. The extended circulation of these nanoreactors enables sustained depletion of asparagine, leading to improved therapeutic outcomes for metastatic breast and pancreatic cancers. Our findings open an avenue for improving the pharmacokinetics of nanomaterials for therapeutic delivery through delicately engineering stable intermolecular structures with holistic cooperativity. A vesicular nanoreactor has increased crosslinks between the constituent polyions for longer blood circulation, and is shown to sensitize solid tumours to asparagine starvation therapy.

The efficacy of traditional chemotherapy in the treatment of non-small cell lung cancer (NSCLC) is often compromised by poor targeting, barriers posed by the tumor microenvironment, and active drug efflux. Furthermore, tumor cells significantly reduce their sensitivity to chemotherapeutic drugs by activating protective autophagy pathways, which is a key mechanism contributing to treatment failure. We designed and synthesized a smart responsive amphiphilic peptide, Pep1, featuring targeted modification with the Arg-Gly-Asp (RGD) peptide and triphenylphosphonium (TPP). Pep1 efficiently coloads paclitaxel (PTX) and hydroxychloroquine (HCQ) (PH/ Pep1) and self-assembles into spherical nanoparticles. In vitro and in vivo experiments confirmed that PH/Pep1 not only efficiently entered lung cancer cells through active targeting to impair mitochondrial function but also inhibited autophagy, thereby preventing the clearance of damaged mitochondria. Through a "damaging mitochondria and inhibiting autophagy" synergistic mechanism, PH/Pep1 ultimately efficiently induced tumor cell apoptosis. Moreover, PH/Pep1 underwent a morphological transformation from nanospheres to nanofibers upon sequential stimulation by alkaline phosphatase (ALP) and reduced glutathione (GSH), which significantly increased drug retention and accumulation within tumor tissues. In a Lewis lung carcinoma (LLC) cell tumorbearing mouse model, PH/Pep1 demonstrated the strongest tumor growth inhibition effect and good biosafety. In summary, the "dual-targeted/dual-responsive" synergistic therapeutic strategy proposed in this study provides a novel approach for designing highly efficient and precise nanodelivery platforms.

Building-integrated photovoltaics (BIPVs) are promising for sustainable urban energy systems but remain constrained by coupled trade-offs among aesthetics, power output, thermal management, and cost. Conventional pigment- or dye-based coloring often reduces power conversion efficiency (PCE) and durability, whereas many structurally colored photovoltaic strategies rely on complex, difficult-to-scale nanostructures. Here, we report a scalable colored photovoltaic strategy based on color-selective polymer multilayer films (PMF-C) derived from a PEN/PMMA platform compatible with continuous coextrusion and layer multiplication. PMF-C generates vivid structural coloration through a selective high-reflection stopband in the visible range while maintaining high transmission over the remaining photovoltaic-relevant spectrum. This spectral selectivity enables color generation and passive thermal regulation by reducing solar heat gain. Integrated with an infrared-emissive EVA encapsulation architecture, PMF-GPV achieves an operating-temperature reduction of up to ∼8.65 °C while retaining ∼74% of the baseline PCE. Beyond experimental demonstration, we establish a data-driven opto-thermo-electrical framework that predicts color, efficiency, and operating temperature prior to fabrication across a broad PMF-C material and structural design space. Parametric sweeps and Pareto analysis identify refractive-index combinations for efficiency-priority, temperature-priority, and balanced designs; notably, under an idealized uniform-thickness design, the PEN/PMMA pair is predicted to retain 86.9% of the reference-cell PCE while reducing the operating temperature by 5.17 K. A machine-learning-assisted inverse-design workflow rapidly maps target colors to feasible PMF-C structural parameters. This work provides both a scalable material platform and a predictive design framework for colored BIPVs with jointly engineered appearance, efficiency, and passive thermal-management performance.

Polymersomes, which are polymer vesicles containing an aqueous cavity enclosed in a polymer membrane, hold enormous potential for biomedical applications. In recent years, enzyme-loaded polymersomes, serving as therapeutic nanoreactors, have drawn substantial interest. A crucial requirement for effective catalytic function is to impart semipermeability to the vesicular membrane while maintaining its role as a protective barrier for encapsulated enzymes. However, achieving both long-term stability and optimal membrane permeability for sustained functionality remains a challenge in many reported examples. In this study, we introduce ROS-responsive polyion complex vesicles (PICsomes) loaded with antioxidant enzymes (catalase) as antioxidative nanoreactors. The intrinsic semipermeability and crosslinked network structure of the membrane enable long-lasting catalytic function of catalase. The nanoreactor exhibits inherent cell-protective properties against oxidative stress in fibroblasts due to the ROS-scavenging ability of polymers. Notably, triggered by ROS, the nanoreactor demonstrates autoregulatory control of redox homeostasis. This is because the cysteamine released by PICsomes not only acts as a free radical scavenger but also facilitates the transport of L-cysteine into cells, thereby enhancing glutathione (GSH) biosynthesis. The results further demonstrate significant long blood circulation of PICsomes loaded with catalase and strong protection effects against bloodstream oxidative stress, paving the way for the further development of truly effective in vivo therapeutics. These findings underscore the potential of the engineered antioxidative nanoreactor with durable functionality as synthetic organelles for cellular protection against oxidative stress.

Near-infrared (NIR) photothermal therapy (PTT) has emerged as a promising modality for cancer treatment due to its minimal invasiveness, precise spatiotemporal control, and potent therapeutic outcomes. However, the clinical application of photothermal agents (PTAs) remains limited by issues such as poor biodegradability, long-term toxicity, and insufficient photothermal conversion efficiency. Herein, we report the development of a novel amphiphilic aza-boron-dipyrromethene (aza-BODIPY)-based photothermal agent, C8-NBDP-OEG4, which self-assembles into monodisperse nanoparticles in aqueous solution. These nanoparticles exhibit excellent chemical and photostability, along with a high photothermal conversion efficiency of 39.8% under 808 nm laser irradiation. To endow the system with multifunctionality, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) was co-encapsulated within the nanoparticles, enabling NIR-triggered NO release. This design achieves a dual-mode therapeutic strategy, combining localized hyperthermia and NO-mediated modulation of the tumor microenvironment, thereby significantly enhancing anticancer efficacy. Importantly, the released NO was found to amplify the photoacoustic (PA) signal intensity, facilitating photoacoustic imaging-guided therapy. Both in vitro and in vivo studies demonstrated pronounced tumor growth inhibition with minimal systemic toxicity. Collectively, our study introduces C8-NBDP-OEG4@NO nanoparticles as a multifunctional theranostic nanoplatform, offering NIR-activated, PA imaging-guided synergistic NO-photothermal therapy and showcasing strong potential for precise and effective cancer treatment.

To overcome the resistance of tumor cells to death through a single pathway, PANoptosis, a novel synergistic mode of cell death, can simultaneously activates pyroptosis, apoptosis, and necroptosis. Most current strategies for inducing PANoptosis focused on amplifying reactive oxygen species (ROS) through exogenous stimuli, while the regulatory role of tumor cell metabolic characteristic in this process has long been overlooked. We propose a ROS-Metabolism dual axis synergistic induction of PANoptosis, simultaneously enhancing antitumor immune responses, and construct a novel bionic nanoplatform named CVOVM. This platform consists of CoVOx nanocakes and the glutamine transporter inhibitor V-9302, with 4T1 cell membranes as camouflage. In tumors, CVOVM initiates a series of catalytic reactions: CoVOx promotes numerous ROS generation, while V-9302 disrupts glutamine metabolism, depleting glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+), thereby triggering the assembly of PANoptosome primarily composed of NLRP3 and NLRC5, which initiates pyroptosis, apoptosis, and necroptosis. The occurrence of PANoptosis promotes immunogenic cell death (ICD) to remodel tumor immunosuppressive microenvironment, and enhances immunotherapy and inhibits lung metastasis. Overall, we present a previously unreported mechanis to achieve the synergistic induction of PANoptosis through ROS amplification and metabolic inhibition, enhancing antitumor immunity, and potentially providing new opportunities and possibilities for combination cancer therapy.

Senescence of activated hepatic stellate cells (aHSCs) is thought to be a promising alternative for limiting hepatic fibrosis. However, uncontrollable accumulation and spread of senescence in neighboring hepatocytes lead to inflammation and steatosis, aggravating fibrosis and even promoting carcinogenesis. To harness senescence for fibrotic treatment, aHSCs-targeted poly (lactic-co-glycolic acid) (PLGA) nanoplatforms have been constructed to integrate senescent induction of aHSCs and senescent reprogramming. Owing to the CD44 aptamer modification, the nanoplatform specifically delivers senescent inducers and small interfering RNAs (siRNAs) that silence nuclear factor-kappa B (NF-κB) in aHSCs, thereby inducing senescence and simultaneously suppressing the production of senescence-associated secretory phenotypes (SASPs) in aHSCs. The senescence of aHSCs decreases their proliferation, and achieves permanent inactivation even upon repeated fibrotic stimulus. Meanwhile, the elimination of SASPs interrupts the vicious cycle of senescent aHSCs with surrounding hepatocytes to decrease senescent and inflammatory accumulation in liver tissues. In vitro and in vivo results confirmed the superior ability of the nanoplatform to inhibit liver fibrosis and control the spread of senescence. Our work provides a nanoplatform for specifically inducing senescence of aHSCs and reveals a promising senescence modulation strategy for the treatment of liver fibrosis.

Polycation-based mRNA delivery systems have an issue with mRNA integrity in the physiological milieu, particularly in blood compartments, despite their vast potential in mRNA therapeutics. Without comprehensive mechanistic analyses, design concepts of polyplexes for in vivo use remain unclear. Herein, we systematically assessed several potential design parameters of polyplex stabilization and provided mechanistic insight into the processes of mRNA degradation loaded in polyplexes, focusing on RNase attack, a process believed to be the leading cause of loss of mRNA integrity loaded into polyplexes. For this purpose, polyplex micelles (PMs) from mRNA and poly(ethylene glycol) (PEG)-polycation block copolymer were used as a platform polyplex system feasible for in vivo application. Elongating PEG from 12-kDa to 42-kDa failed to improve RNase stability despite a plausible increase in the PEG layer thickness on the PM surface. Meanwhile, the elongation of polycation segments and a subtle but critical modulation in the side chain of polycation structure, i.e., changing from poly(l-lysine) to poly(l-ornithine), significantly improved the resistance of cargo mRNA against RNase attack. Nonetheless, nearly 50 % of mRNA was degraded even in the optimal PM formulation after 30 min incubation in 50 % serum. Plausible mechanisms of mRNA degradation include (i) dissociation of PM structure by polyion exchange reaction with anionic biomolecules in serum to release mRNA, followed by RNase attack and (ii) RNase penetration into PM interior to directly attack cargo mRNA without PM dissociation. A series of mechanistic experiments revealed that mRNA was still settled in the PMs even after a loss of mRNA integrity by 50 % serum treatment, indicating the latter to be the main reason for the degradation of cargo mRNA. Further, the integrity of PM structure and cargo mRNA in circulating blood was evaluated separately in mice. Intravital microscopic observation of mRNA complexation status using fluorescence resonance energy transfer (FRET) indicates prolonged mRNA retention in the PM structure even under blood circulation. In contrast, quantitative PCR-based evaluation of mRNA integrity revealed the occurrence of prompt mRNA degradation in the same condition. This study highlights that PM structure is robust enough against dissociation under blood circulation. Yet, the remaining challenge toward optimizing PM-based mRNA delivery systems for systemic application is to build a functionality to prevent RNase invasion into the polyplex core storing cargo mRNA.

Prodrug cancer nanomedicines have emerged as promising strategies to enhance drug solubility, reduce systemic toxicity, and improve tumor accumulation. However, the therapeutic efficacy of prodrug systems remains limited by suboptimal in vivo activation, resulting in non-functional accumulation at disease sites. Herein, we report the design of enzyme-powered, ultra-pH-sensitive micellar nanoreactors that orchestrate a tumor-specific, cascade-amplified prodrug activation mechanism for synergistic oxidation-chemo-immunotherapy. By encapsulating glucose oxidase (GOD) within paclitaxel-conjugated polymeric micelles, the nanoreactors exploit the acidic tumor microenvironment to initiate localized oxidative bursts, which not only amplify reactive oxygen species (ROS) generation but also accelerate pro-paclitaxel cleavage to release active paclitaxel in situ. The piperidine-functionalized nanoreactor architecture exhibits a tumor-acidity-triggered spatial rearrangement that alleviates steric hindrance, thereby enhancing enzymatic accessibility and catalysis while maintaining structural integrity. In vitro studies reveal potent cytotoxicity and immunogenic cell death (ICD) induction under acidic conditions, while in vivo experiments demonstrate efficient tumor-specific prodrug activation, oxidative microenvironment remodeling, and enhanced tumor accumulation. Notably, combining pro-paclitaxel nanoreactors with anti-PD-1 immune checkpoint blockade achieves robust tumor regression and significant survival extension in an orthotopic pancreatic cancer model. This study highlights the therapeutic potential of nanoreactor-driven cascade-amplified prodrug activation as a straightforward strategy to overcome pharmacological and immunological barriers in pancreatic cancer treatment.

Controlling the end-groups of biocompatible polymers is crucial for enabling polymer-based therapeutics and nanomedicine. Typically, end-group diversification is a challenging and time-consuming endeavor, especially for polymers prepared via ionic polymerization mechanisms with limited functional group tolerance. In this study, we present a facile end-group diversification approach for poly(2-oxazoline)s (POx), enabling quick and reliable production of heterotelechelic polymers to facilitate POxylation. The approach relies on the careful tuning of reaction parameters to establish differential reactivity of a pentafluorobenzyl initiator fragment and the living oxazolinium chain-end, allowing the selective introduction of N-, S-, O-nucleophiles via the termination of the polymerization, and a consecutive nucleophilic para-fluoro substitution. The value of this approach for the accelerated development of nanomedicine is demonstrated through the synthesis of well-defined lipid-polymer conjugates and POx-polypeptide block-copolymers, which are well-suited for drug and gene delivery. Furthermore, we investigated the application of a lipid-POx conjugate for the formulation and delivery of mRNA-loaded lipid nanoparticles for immunization against the SARS-COV-2 virus, underscoring the value of POx as a biocompatible polymer platform.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD. The potential of adrenoceptor-blockade strategy was explored for reprogromming the activated hepatic stellate cells and reducing hepatic lipid accumulation in the treatment of NAFLD. A biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was tailored for achieving precise delivery of retinoic acid and adrenoceptor antagonists as well as consuming ROS to provide anti-inflammatory benefits. The biomimetic nanoplatform integrating adrenoceptor blockade exhibits excellent ability to reduce liver steatosis and alleviate inflammation and fibrosis, thereby achieving enhanced NAFLD treatment.

Irregular Li deposition is the major reason for poor reversibility and cycle instability in Li metal batteries, even leading to safety hazards, the causes of which have been extensively explored. The structural disconnection induced by completely dissolving Li in the traditional testing protocol is a key factor accounting for irregular Li growth during the subsequent deposition process. Herein, the critical role played by the structural connectivity of electrochemical Li reservoir in subsequent Li deposition behaviors is elucidated and a morphology-performance correlation is established. The structural connection and resultant well-distributed morphology of the in situ electrochemical Li reservoir ensure efficient electron transfer and Li+ diffusion pathway, finally leading to homogenized Li nucleation and growth. Tailoring the geometry of Li reservoir can improve the coulombic efficiency and cyclability of anode-free Li metal batteries by optimizing Li deposition behavior.

Simple and sensitive detection of cardiac biomarkers is of great significance for early diagnosis and prevention of acute myocardial infarction (AMI). Here, a ratiometric fluorescent nanohybrids probe (AuNCs-QDs) was synthesized through the coupling of bovine serum albumin-functionalized gold nanoclusters (AuNCs) with CdSe/ZnS quantum dots (QDs) to realize simple and sensitive detection of cardiac biomarker myoglobin (Mb). The AuNCs-QDs probe shows purple fluorescence under UV light, with two emission peaks at 468 nm and 630 nm belonging to QDs and AuNCs, respectively. Importantly, the presence of Mb caused fluorescence quenching of the blue-emitting QDs, thereby inhibiting the fluorescence resonance energy transfer (FRET) process between QDs and AuNCs, and reducing the fluorescence intensity ratio (F 468 /F 630 ) of AuNCs-QDs probe effectively. As the concentration of Mb increases, the ratiometric fluorescent probe also exhibits a visible fluorescence color change. The detection limit was as low as 4.99 ng/mL, and the response of the probe to Mb showed a good linear relationship up to 0.52 mg/mL. Moreover, the probe has excellent specificity for Mb. Besides, the AuNCs-QDs has been applied to detect Mb of urine samples. More importantly, we also developed an AuNCs-QDs probe modified smartphone-aided paper-based strip for on-site monitoring of Mb. As far as we know, this is the first report of a smartphone-aided paper-based strip for on-site quick monitoring of Mb, which provides a useful approach for AMI biomarker monitoring and may can be extended to other medical diagnostics.

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.

EDITORIAL article Front. Bioeng. Biotechnol., 18 August 2023Sec. Nanobiotechnology Volume 11 - 2023 | https://doi.org/10.3389/fbioe.2023.1274210

Nanomedicines improve drug bioavailability, the dose–response relationship, targeting ability, efficacy and safety compared to conventional freely administered drugs. Nonetheless, despite their success as carriers for SARS-CoV-2 vaccines, clinical use of nanomedicines is still limited, probably caused by mismatches between animal models and humans. In this Review, we propose that improving blood circulation, biodistribution and tissue accessibility could help improve the clinical translation of nanomedicines. Specifically, we emphasize control of the pharmacokinetics relevant to the administration route, therapeutic targets in tissues and cells, and the drug payloads. Furthermore, we analyse the clearance and distribution of nanomedicines in preclinical and clinical studies, highlighting the biological barriers determining their in vivo performance. Finally, we present engineering strategies, such as size tuning, active targeting for transcytosis, external stimuli and biological shifts, to overcome these barriers.

3-Amino-4-amidoximinofurazan (AAOF) is an important precursor for the synthesis of high energy furazan energetic materials.

The stealth effect plays a central role on capacitating nanomaterials for drug delivery applications through improving the pharmacokinetics such as blood circulation, biodistribution, and tissue targeting. Here based on a practical analysis of stealth efficiency and a theoretical discussion of relevant factors, we provide an integrated material and biological perspective in terms of engineering stealth nanomaterials. The analysis surprisingly shows that more than 85% of the reported stealth nanomaterials encounter a rapid drop of blood concentration to half of the administered dose within 1 h post administration although a relatively long β-phase is observed. A term, pseudo-stealth effect, is used to delineate this common pharmacokinetics behavior of nanomaterials, that is, dose-dependent nonlinear pharmacokinetics because of saturating or depressing bio-clearance of reticuloendothelial system (RES). We further propose structural holism can be a watershed to improve the stealth effect; that is, the whole surface structure and geometry play important roles, rather than solely relying on a single factor such as maximizing repulsion force through polymer-based steric stabilization (e.g., PEGylation) or inhibiting immune attack through a bio-inspired component. Consequently, engineering delicate structural hierarchies to minimize attractive binding sites, that is, minimal charges/dipole and hydrophobic domain, becomes crucial. In parallel, the pragmatic implementation of the pseudo-stealth effect and dynamic modulation of the stealth effect are discussed for future development.