Atherosclerosis (AS) is a major contributor to cardiovascular diseases worldwide, and alleviating inflammation is a promising strategy for AS treatment. Here, we report molecularly engineered M2 ...macrophage‐derived exosomes (M2 Exo) with inflammation‐tropism and anti‐inflammatory capabilities for AS imaging and therapy. M2 Exo are derived from M2 macrophages and further electroporated with FDA‐approved hexyl 5‐aminolevulinate hydrochloride (HAL). After systematic administration, the engineered M2 Exo exhibit excellent inflammation‐tropism and anti‐inflammation effects via the surface‐bonded chemokine receptors and the anti‐inflammatory cytokines released from the anti‐inflammatory M2 macrophages. Moreover, the encapsulated HAL can undergo intrinsic biosynthesis and metabolism of heme to generate anti‐inflammatory carbon monoxide and bilirubin, which further enhance the anti‐inflammation effects and finally alleviate AS. Meanwhile, the intermediate protoporphyrin IX (PpIX) of the heme biosynthesis pathway permits the fluorescence imaging and tracking of AS.
M2 macrophage‐derived exosomes molecularly engineered with the drug hexyl 5‐aminolevulinate hydrochloride (HAL) can actively target and transmigrate to atherosclerotic lesions, wherein the biosynthesis and metabolism of heme induced by HAL produces CO and bilirubin. This, along with the anti‐inflammatory cytokines in exosomes, acts to significantly alleviate atherosclerosis.
Extracellular vesicles (EVs) hold great potential in both disease treatment and drug delivery. However, accurate drug release from EVs, as well as the spontaneous treatment effect cooperation of EVs ...and drugs at target tissues, is still challenging. Here, an engineered self‐activatable photo‐EV for synergistic trimodal anticancer therapy is reported. M1 macrophage‐derived EVs (M1 EVs) are simultaneously loaded with bis2,4,5‐trichloro‐6‐(pentyloxycarbonyl) phenyl oxalate (CPPO), chlorin e6 (Ce6), and prodrug aldoxorubicin (Dox‐EMCH). After administration, the as‐prepared system actively targets tumor cells because of the tumor‐homing capability of M1 EVs, wherein M1 EVs repolarize M2 to M1 macrophages, which not only display immunotherapy effects but also produce H2O2. The reaction between H2O2 and CPPO generates chemical energy that activates Ce6, creating both chemiluminescence for imaging and singlet oxygen (1O2) for photodynamic therapy (PDT). Meanwhile, 1O2‐induced membrane rupture leads to the release of Dox‐EMCH, which is then activated and penetrates the deep hypoxic areas of tumors. The synergism of immunotherapy, PDT, and chemotherapy results in potent anticancer efficacy, showing great promise to fight cancers.
Self‐activatable photo‐extracellular vesicles are constructed by loading M1‐macrophage‐derived EVs with bis2,4,5‐trichloro‐6‐(pentyloxycarbonyl)phenyl oxalate, chlorin e6, and prodrug aldoxorubicin. These skillfully engineered extracellular vesicles can actively target tumors owing to their inherent tumor‐homing ability, wherein they exhibit potent trimodal therapy effects in an intersynergistic and self‐controllable way, attributed to the interaction between the engineered EV and the special tumor microenvironment.
Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize ...responsive exosome nano‐bioconjugates for cancer therapy. Azide‐modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne‐modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH‐sensitive linkers. After systemic administration, the nano‐bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic‐imine bonds of the nano‐bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished “don't eat me” signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro‐tumoral M2 to anti‐tumoral M1.
Ok, take a bite: Responsive exosome nano‐bioconjugates were constructed by engineering M1 exosomes with aCD47 and aSIRPα linked with a pH‐sensitive bond. After systemic administration, the synergism of specific targeting by aCD47, blocking of “don't eat me” signaling by aCD47 and aSIRPα, and M2 reprogramming by M1 exosomes resulted in a potent anticancer effect.
Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which ...subtype patients will be responsive to checkpoint blockade are not fully understood.
We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.
We observed that
mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the
comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of
Meanwhile,
or
-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that
or
mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that
or
mutation patients, especially those with co-occurring
mutations, showed remarkable clinical benefit to PD-1 inhibitors.
This work provides evidence that
and
mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy.
.
Hypoxic microenvironment severely reduces therapeutic efficacy of oxygen‐dependent photodynamic therapy in solid tumor due to the hampered cytotoxic oxygen radicals generation. Herein, a ...biocompatible nanoparticle (NP) is developed by combining bovine serum albumin, indocyanine green (ICG), and an oxygen‐independent radicals generator (AIPH) for efficient sequential cancer therapy, denoted as BIA NPs. Upon near‐infrared irradiation, the photothermal effect generated by ICG will induce rapid decomposition of AIPH to release cytotoxic alkyl radicals, leading to cancer cell death in both normoxic and hypoxic environments. Moreover, such nanosystem provides the highest AIPH loading capacity (14.9%) among all previously reported radical nanogenerators (generally from 5–8%). Additionally, the aggregation‐quenched fluorescence of ICG molecules in the NPs can be gradually released and recovered upon irradiation enabling real‐time drug release monitoring. More attractively, these BIA NPs exhibit remarkable anticancer effects both in vitro and in vivo, achieving 100% tumor elimination and 100% survival rate among 50 days treatment. These results highlight that this albumin‐based nanoplatform is promising for high‐performance cancer therapy circumventing hypoxic tumor environment and possessing great potential for future clinical translation.
A biocompatible free radical nanogenerator is developed based on albumin, indocyanine green, and thermal‐labile molecules for effective hypoxic cancer therapy. Under laser irradiation, this nanoagent can generate toxic free radicals in both normoxia and hypoxia. Meanwhile, the nanogenerator provides a high drug loading capability and real‐time drug release monitoring ability a which enables it with multifunctionality and high therapeutic performance.
Nanodelivery systems (NDSs) provide promising prospects for decreasing drug doses, reducing side effects, and improving therapeutic effects. However, the bioapplications of NDSs are still compromised ...by their fast clearance, indiscriminate biodistribution, and limited tumor accumulation. Hence, engineering modification of NDSs aiming at promoting tumor‐specific therapy and avoiding systemic toxicity is usually needed. An NDS integrating various functionalities, including flexible camouflage, specific biorecognition, and sensitive stimuli‐responsiveness, into one sequence would be “smart” and highly effective. Herein, we systematically summarize the related principles, methods, and progress. At the end of the review, we predict the obstacles to precise nanoengineering and prospects for the future application of NDSs.
The fast clearance and limited tumor accumulation seriously imperil practical applications of nano delivery systems (NDSs). Therefore, the additional engineering modification is usually needed. An NDS integrating flexible camouflage, specific bio‐recognition, and sensitive stimuli‐responsiveness into one sequence would be “smart” and highly effective. Hence, we systematically summarize the related principles, methods, and progress; meanwhile, provide instructive prospection.
Extracellular vesicles (EVs) have shown great potential in drug delivery, disease diagnosis, and treatment owing to their versatile native features and functions. RNA interference (RNAi) therapeutics ...that block the programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) pathway have attracted increasing interest for the treatment of various cancers. Here, immunoregulatory EVs are developed by decorating M1‐macrophage‐derived EVs (M1 EV) with vesicular stomatitis virus glycoprotein (VSV‐G), a pH‐responsive viral fusion protein, and electroporating anti‐PD‐L1 siRNA (siPD‐L1) into the EVs. After administration to CT26 tumor‐bearing mice, this virus‐mimic nucleic acid engineered EVs (siRNA@V‐M1 EV) can target tumor tissues, which is attributed to the natural tumor‐homing property of M1 EV. Then, the fusion of VSV‐G with cells facilitates the direct release of siPD‐L1 into the cytoplasm and triggers robust gene silencing, leading to the efficient block of PD‐L1/PD‐1 interaction and then the elevation of CD8+ T cell population. Meanwhile, the M1 EVs and IFN‐γ secreted by the CD8+ T cells promote the repolarization of M2 tumor‐associated macrophages to M1 macrophages. The combination of PD‐L1/PD‐1 pathway blocking, T cell recognition reconstructing, and M1 macrophage repolarization via multifunctional EVs can achieve satisfactory antitumor efficacy in this tumor model, showing potential as a new modality to fight cancers.
Immunoregulatory extracellular vesicles are constructed by decorating M1 macrophage‐derived extracellular vesicles (EVs) with fusogenic virus protein VSV‐G and electroporating anti‐PD‐L1 siRNA. This engineered EVs can actively target tumors and then directly release siRNA to the cytoplasm via VSV‐G induced membrane fusion. A potent tumor immunotherapy effect is thus achieved through restoring T cell immune surveillance and augmenting M1 macrophage phagocytosis.
Positioning essential elements of photodynamic therapy (PDT) near to mitochondria can conquer the rigorous spatiotemporal limitations of reactive oxygen species (ROS) transfer and make considerable ...differences in PDT. However, precise accumulation of photosensitizer (PS) and oxygen within mitochondria is still challenging. We simultaneously encapsulated hexyl 5‐aminolevulinate hydrochloride (HAL) and 3‐bromopyruvic acid (3BP) into microparticles collected from X‐ray‐irradiated tumor cells (X‐MP). After systemic administration, the developed HAL/3BP@X‐MP can specifically target and recognize tumor cells, where HAL induces efficient accumulation of PpIX in mitochondria via the intrinsic haem biosynthetic pathway. Meanwhile, 3BP remarkably increases the oxygen supply by inhibiting mitochondrial respiration. The accurate co‐localization and prompt encounter of PpIX and oxygen produce sufficient ROS to directly disrupt mitochondria, resulting in significantly improved PDT outcomes.
Accurate co‐localization of PpIX and O2: HAL and 3BP‐loaded microparticles specifically target and recognize tumor cells, wherein HAL induces the biosynthesis of PpIX in mitochondria and 3BP reduces the mitochondria oxygen consumption. The precise co‐localization of PpIX and O2 produces sufficient singlet oxygen to directly disrupt mitochondria, significantly improving PDT.
Organic near‐infrared room temperature phosphorescence (RTP) materials offer remarkable advantages in bioimaging due to their characteristic time scales and background noise elimination. However, ...developing near‐infrared RTP materials for deep tissue imaging still faces challenges since the small band gap may increase the non‐radiative decay, resulting in weak emission and short phosphorescence lifetime. In this study, fused‐ring pyrrole‐based structures were employed as the guest molecules for the construction of long wavelength emissive RTP materials. Compared to the decrease of the singlet energy level, the triplet energy level showed a more effectively decrease with the increase of the conjugation of the substituent groups. Moreover, the sufficient conjugation of fused ring structures in the guest molecule suppresses the non‐radiative decay of triplet excitons. Therefore, a near‐infrared RTP material (764 nm) was achieved for deep penetration bioimaging. Tumor cell membrane is used to coat RTP nanoparticles (NPs) to avoid decreasing the RTP performance compared to traditional coating by amphiphilic surfactants. RTP NPs with tumor‐targeting properties show favorable phosphorescent properties, superior stability, and excellent biocompatibility. These NPs are applied for time‐resolved luminescence imaging to eliminate background interference with excellent tissue penetration. This study provides a practical solution to prepare long‐wavelength and long‐lifetime organic RTP materials and their applications in bioimaging.
The development of room‐temperature phosphorescence (RTP) nano‐probes with long emission wavelength faces challenges. In this work, organic RTP materials with near‐infrared emission have been designed and cell membrane encapsulation has been used to optimize the nanomaterial process, achieving high signal‐to‐background ratio and imaging penetration depth.
A novel biomimetic immuno‐magnetosome (IMS) is developed by coating a leukocyte membrane (decorated with anti‐epithelial cell‐adhesion molecule antibody) on a magnetic nanocluster. In addition to the ...good stability and magnetic controllability, the IMS also exhibits satisfactory binding avidity to circulating tumor cells but stealth property to leukocytes. As a result, rare tumor cells can be effectively enriched with undetectable leukocyte background.
