Nanotechnologies meeting natural sources:Engineered lipoproteins for precise brain disease theranostics

Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity,from preventive and diagnostic to therapeutic fields.Lipoproteins,because of their inherent blood-brain barrier permeability and lesion-homing capability,have been identified as promising strategies for high-performance theranostics of brain diseases.However,the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes,which can be critical for individual therapeutics and clinical translation.To address these issues,lipoprotein-inspired nano drug-delivery systems(nano-DDSs),which have been learned from nature,have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions.In this review,the barriers in brain disease treatment,advantages of state-of-the-art lipoprotein-inspired nano-DDSs,and bio-interactions of such nano-DDSs are highlighted.Furthermore,the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized.Specifically,the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed.Finally,the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles,such as exosomes,cell membranes,and bacteria,are discussed.

Bioengineering extracellular vesicles as novel nanocarriers towards brain disorders

Despite noteworthy technological progress and promising preclinical trials,brain disorders are still the leading causes of death globally.Extracellular vesicles(EVs),nano-/micro-sized membrane vesicles carrying bioactive molecules,are involved in cellular communication.Based on their unique properties,including superior biocompatibility,non-immunogenicity,and blood-brain barrier(BBB)penetration,EVs can shield their cargos from immune clearance and transport them to specific site,which have attracted increasing interests as novel nanocarriers for brain disorders.However,considering the limitations of native EVs,such as poor encapsulation efficiency,inadequate targeting capability,uncontrolled drug release,and limited production,researchers bioengineer EVs to fully exploit the clinical potential.Herein,this review initially describes the basic properties,biogenesis,and uptake process of EVs from different subtypes.Then,we highlight the application of EVs derived from different sources for personalized therapy and novel strategies to construct bioengineered EVs for enhanced diagnosis and treatment of brain disorders.Besides,it also presents a systematic comparison between EVs and other brain-targeted nanocarriers.Finally,existing challenges and future perspectives of EVs have been discussed,hoping to bolster the research from benchtop to bedside.

Gather wisdom to overcome barriers:Well-designed nano-drug delivery systems for treating gliomas

Due to the special physiological and pathological characteristics of gliomas,most therapeutic drugs are prevented from entering the brain.To improve the poor prognosis of existing therapies,researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy.Although these strategies can be used clinically to overcome the blood-brain barrier(BBB),the accurate delivery of drugs to the glioma lesions cannot be ensured.Nano-drug delivery systems(NDDS)have been widely used for precise drug delivery.In recent years,researchers have gathered their wisdom to overcome barriers,so many well-designed NDDS have performed prominently in preclinical studies.These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions,drug release in response to the glioma microenvironment,biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein,and carriers created according to the active ingredients of traditional Chinese medicines.We reviewed these well-designed NDDS in detail.Furthermore,we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy,and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

Lipoprotein-biomimetic nanostructure enables tumor-targeted penetration delivery for enhanced photo-gene therapy towards glioma

Glioma is one of the most malignant primary tumors affecting the brain.The efficacy of therapeutics for glioma is seriously compromised by the restriction of blood-brain barrier(BBB),interstitial tumor pressure of resistance to chemotherapy/radiation,and the inevitable damage to normal brain tissues.Inspired by the natural structure and properties of high-density lipoprotein(HDL),a tumor-penetrating lipoprotein was prepared by the fusion tLyP-1 to apolipoprotein A-I-mimicking peptides(D4F),together with indocyanine green(ICG)incorporation and lipophilic small interfering RNA targeted HIF-1α(siHIF)surface anchor for site-specific photo-gene therapy.tLyP-1 peptide is fused to HDL-surface to facilitate BBB permeability,tumor-homing capacity and-site accumulation of photosensitizer and siRNA.Upon NIR light irradiation,ICG not only served as real-time targeted imaging agent,but also provided toxic reactive oxygen species and local hyperthermia for glioma phototherapy.The HIF-1αsiRNA in this nanoplatform downregulated the hypoxia-induced HIF-1αlevel in tumor microenvironment and enhanced the photodynamic therapy against glioma.These studies demonstrated that the nanoparticles could not only efficiently across BBB and carry the payloads to orthotopic glioma,but also modulate tumor microenvironment,thereby inhibiting tumor growth with biosafety.Overall,this study develops a new multifunctional drug delivery system for glioma theranostic,providing deeper insights into orthotopic brain tumor imaging and treatment.