Recent findings indicate that nanoparticles (NPs) can mediate targeted protein degradation (TPD) with versatility and efficiency. Studies have shown that ligand-modified NPs can effectively degrade both extracellular and intracellular proteins of interest through an autolysosome-involved degradation pathway, independent of both NPs and ligand types. This phenomenon, where ligand-modified NPs shuttle proteins of interest towards degradation, may prompt researchers to rethink the design of ligand-NPs, incorporating TPD as an additional functionality beyond conventional delivery. Moreover, this approach has the potential to revolutionize the field of TPD by transitioning from labour-intensive, case-specific designs to a broadly adaptable ‘plug-and-play’ platform that makes full use of the in vivo delivery potential of NPs. This Perspective discusses the evolution of current TPD tools, the desired features of next-generation technologies, and the potential and challenges of NP-mediated targeting chimeras for TPD, highlighting emerging trends and raising awareness of this promising field. This Perspective underscores how ligand-installed nanoparticles can transcend their delivery role by incorporating targeted protein degradation (TPD) functionality, with nanoparticle-mediated-targeting chimeras, broadening the TPD toolkit.

Near-infrared (NIR) fluorescence probes featuring ultralarge Stokes shifts and efficient aggregate-state luminescence are highly desirable for bioimaging yet remain scarce due to formidable synthetic challenges and intricate photophysical modulation. We report a facile one-step click reaction to synthesize a tetracyanoquinodimethane-derived NIR probe (TNQ2) that overcomes the long-standing nonfluorescence limitation while achieving an unprecedented 445-nanometer Stokes shift. TNQ2 self-assembles into the smallest-sized two-dimensional J-aggregates (sub-160 nanometers) with a red-shift absorption from 545 to 725 nanometers and aggregation-enhanced emission around 1000 nanometers. The radiative/nonradiative modulation balances the fluorescence/photothermal/photodynamic effect to support high-sensitivity NIR-II fluorescence imaging-guided precise glioma resection and postoperative phototherapy to substantially extend survival in orthotopic glioma models. Our molecule/nanoengineering strategy establishes a transformative paradigm for developing advanced NIR phototheranostics for brain diseases.

Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy to eliminate disease-associated proteins that are inaccessible to conventional inhibition. Among TPD approaches, nanoparticle-mediated degradation, particularly through nanoparticle-mediated targeting chimerics (NPTACs) that induce receptor-mediated endocytosis and lysosomal degradation, offers unique advantages in modular design, target selectivity, and delivery potential. However, the complexity of these systems, determined by factors including particle size, surface charge, PEGylation, and ligand properties, poses significant challenges in predicting which formulations will effectively mediate intracellular trafficking and protein degradation. This perspective proposes artificial intelligence (AI) as a transformative tool to enable rational, predictive, and personalized NPTAC design. By integrating curated datasets, machine learning, generative modeling, and mechanistic insights, AI can navigate vast design spaces and accelerate translation. We outline key opportunities, challenges, and a future vision for intelligent, patient-tailored degrader nanomedicines.

In the precision-medicine era, rare diseases must not be sidelined in translational infrastructure. The Mr. Cai Lei-led "Ice-Breaking Team" turns an amyotrophic lateral sclerosis patient community into a sustainable ecosystem, realigning philanthropy, data, and research and development to reshape rare-disease pipelines and guide precision therapies, offering a replicable blueprint for rare-disease strategies.

Liposomes represent versatile drug delivery shuttles in clinics for cancer therapy. Nevertheless, traditional PEG-modified liposomes encounter difficulties, including (1) poor blood-brain barrier (BBB) transcytosis and tumor targeting without ligand-decoration; (2) accelerated blood clearance (ABC) resulting from anti-PEG antibodies and complement proteins. To overcome these challenges, we employed a ligand-free, BBB-permeable, and glioblastoma (GBM)-targeting zwitterionic polyphosphorylcholine (PMPC)-modified liposomal formulation for siRNA delivery (PMPC-Lipo@siRNA). PMPC-modified formulation leverages interactions with nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) to achieve effective BBB transcytosis and targeted tumor accumulation. Unlike anti-PEG antibodies-induced immunogenicity, PMPC modification successfully circumvents opsonin recognition, which potentially translates into their extended blood circulation and improved therapeutic responses. By targeting the PLK1 oncogene, PMPC-Lipo@siPLK1 effectively induced apoptosis through PLK1 inhibition, significantly extending the median survival of mice in both orthotopic human U87MG and patient-derived CSC2 stem cell xenograft models. Overall, PMPC-modified liposomes provide an effective ligand-free platform for GBM-targeted siRNA delivery by combining prolonged systemic circulation with intrinsic brain-targeting capability, highlighting their potential for RNAi-based therapy against GBM.

Immunotherapy has achieved remarkable clinical success, yet its efficacy remains constrained by immune escape, acquired resistance, and the immunosuppressive tumor microenvironment (TME). A major contributor is the persistent presence of immunosuppressive proteins within tumors and immune cells. Current therapies primarily rely on functional blockade rather than protein elimination, allowing these proteins to continuously sustain immune suppression and drive resistance. Moreover, many immunosuppressive proteins remain “undruggable” due to the lack of suitable binding pockets. Targeted protein degradation (TPD) offers a powerful alternative by selectively eliminating disease-causing proteins. Recent advances have enabled the degradation of intracellular, membrane, and extracellular proteins, significantly expanding the therapeutic landscape. By removing proteins rather than transiently inhibiting them, TPD can achieve more durable antitumor immune responses with reduced resistance. Furthermore, nanosystems enhance TPD by facilitating efficient delivery and promoting protein degradation. This review summarizes recent progress in TPD-based cancer immunotherapy and discusses future directions for next-generation platforms.

Hyperphosphorylated Tau aggregates are a central pathological hallmark of Alzheimer’s disease (AD), yet no approved therapy directly targets this process. mRNA therapeutics provide a transient and non-viral option but are limited by the blood-brain barrier (BBB). TRIM11 is an ATP-independent disaggregase that dissolves pathological Tau fibrils and promotes proteasomal clearance. Here, a ligand-free lipid nanoparticle (PLNP) is developed with zwitterionic, acetylcholine-mimetic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) as a core component and leverages interactions with nAChRs and chTs to enable BBB transcytosis. Systemic PLNP delivery of TRIM11 mRNA yields an 8.1-fold increase in hippocampal accumulation and >30-fold higher neuronal transfection than unformulated mRNA. In 3×Tg-AD mice, PLNP-mTRIM11 reduces P-Ser396- and AT8-positive Tau aggregates, attenuates neuroinflammation, restores synaptic/neuronal integrity, and improves cognition and nest building for ≥3 months. Early prophylactic dosing prevents Tau pathology and preserves cognitive function, supporting PLNP-mTRIM11 for tauopathy therapy.

Single-cell-level resolution tumor therapy represents an advanced strategy against glioblastoma but lacks suitable theranostic agents. Here, we developed a spatiotemporal-switchable, two-dimensional (2D), bismuthene-based second near-infrared window (NIR-II) nanozyme. In this platform, the bismuthene scaffold simultaneously directed the assembly of indocyanine green (ICG) into ordered J-aggregates and anchored monodispersed platinum (Pt) atoms. The resulting J-aggregates acted as an optical antenna with a long-wavelength absorption peak at 895 nanometers and high photobleaching resistance of 78.0%, enabling the identification of single tumor cells with a resolution of 44.3 micrometers at 1350 nanometers for precise glioma resection. Postoperatively, the spatiotemporal-switchable function was activated for therapeutic intervention, in which the photothermal effect amplified the original efficiency of the catalase-like activity of Pt atoms by threefold, driving a surge in intracellular oxygen to combat tumor hypoxia. Upon 808-nanometer irradiation, the induced oxygen release in the tumor microenvironment amplified ICG-mediated photodynamic therapy, and combined with bismuthene-mediated photothermal therapy, it effectively inhibited residual tumors. In an orthotopic glioma mouse model, this approach minimized recurrence and achieved increased survival without inducing neurological or motor deficits. This work provides an atomic-level and molecular-level design blueprint for NIR-II nanotheranostic agents, paving the way toward clinical translation of single-cell-level precision medicine for brain malignancies.

Glioblastoma (GBM), one of the most aggressive and lethal brain tumors, remains incurable with a poor clinical prognosis. Cancer vaccines hold great potential for preventing malignant tumors, including GBM. However, conventional GBM vaccines face significant limitations, such as inefficient antigen delivery, safety concerns, and high production costs. Here, we have successfully developed a natural vaccine (DEX/GM) based on dendritic cell-derived exosomes (DEX) coated with glioblastoma cell membranes (GM) that can efficiently stimulate systemic antitumor immune responses via enhancing antigen uptake by antigen-presenting cells (APCs) and enabling sustained antigen release. The high density of tumor-associated antigens on the cell membrane surface, combined with the intrinsic immunogenicity of DEX, promotes long-term immune memory. Following an optimized three-dose vaccination regimen, DEX/GM significantly induced cytokine expression and triggered the generation and activation of immune cells, including cytotoxic T cells, mature dendritic cells, and memory T cells. Importantly, this vaccination schedule demonstrated superior preventative GBM effects in mice, as all vaccinated mice survived up to 150 days even when challenged up to three times via intracranial injection of exponentially growing GL261-luc GBM tumor cells. Therefore, our all-natural tumor vaccine may offer a versatile strategy for the prevention of GBM, and potentially other malignant tumors, paving the way for promising future clinical applications.

Chronic neuroinflammation is a known etiopathogenic factor in neurodegenerative disease. While cannabidiol (CBD) has demonstrated anti-inflammatory effects, unfavorable pharmacokinetics and poor blood-brain barrier (BBB) permeability lead to low brain exposure. Here, we greatly improve the efficacy of CBD to treat neuroinflammation by incorporating CBD in a BBB-permeable glucose nanoparticle (GNPs) that by design also incorporates tissue-targeting moieties and uses reactive oxygen species responsive polymer to selectively target neuroinflammatory lesions. We achieved a high drug concentration over 20 times higher than naked cargo and demonstrate potent therapeutic effects in two mouse models of neuroinflammatory disease. Mechanistically, disease amelioration resulted from repolarizing microglia from the neurotoxic M1 to the neuroprotective M2 phenotype, leading to neuronal cell regeneration by enhanced secretion of brain derived neurotropic and anti-inflammatory factors. Our approach for brain targeted CBD delivery may provide a versatile platform for treating other CNS disorders characterized by neuroinflammation.

Targeted protein degradation (TPD) has reshaped therapeutic strategy by catalytically eliminating pathogenic proteins through engagement with endogenous proteolytic systems. In contrast to conventional inhibitors that transiently block enzymatic activity, TPD achieves durable target silencing by physically removing the protein entirely, thereby overcoming resistance mechanisms and extending therapeutic durability. This approach enables the pharmacological modulation of previously "undruggable" entities, such as transcription factors and scaffolding proteins, that lack canonical binding pockets. However, clinical translation of existing TPD platforms, including PROTACs and molecular glues, remains limited by poor bioavailability, off-target toxicity, and suboptimal tissue selectivity. Nanoparticle-assisted targeted protein degraders (NanoTACs) offer a compelling solution by coupling the catalytic efficiency of TPD with the spatial precision and tunability of nanotechnology. Through rational nanocarrier engineering, NanoTACs overcome key limitations of small-molecule degraders, including poor solubility, rapid systemic clearance, and inadequate targetability, while enabling direct and selective degradation of pathogenic proteins with minimal structural modification. This integration affords programmable control of biodistribution, cellular uptake, and release kinetics, as well as microenvironment-responsive degradation that is difficult to achieve with traditional modalities. Beyond functioning as delivery vehicles, NanoTACs actively recruit degradation machinery, modulate intracellular proteostasis, and permit synergistic co-delivery of therapeutic payloads. Emerging data demonstrate their capacity to degrade oncogenic drivers, suppress inflammatory signaling, and eliminate pathological protein aggregates across diverse disease models. This Review delineates the conceptual foundations, design principles, and translational prospects of NanoTACs, positioning them as a next-generation platform at the intersection of nanomedicine, chemical biology, and precision oncology.

Tumor spheroids, the most widely used model of 3D cell culture, have emerged as a viable platform for assessing drug responses. However, high-throughput validation of novel drugs using tumor spheroids remains hindered by the challenges in generating large-scale, homogeneous, and functionally relevant spheroids. Here, a flow-focusing droplet microfluidic platform is developed for high-throughput generation of uniform tumor spheroids, producing over 50 000 droplets within 5 min, with each microdroplet serving as an individual bioreactor for spheroid formation. The initial size of the tumor spheroids is tuned based on cell concentration and water-to-oil flow rate ratio during microdroplet generation. After being released from the microdroplets, the 3D tumor spheroids continue growing, reaching diameters exceeding 300 µm. The growth and functional characteristics of the spheroids are examined both in a liquid environment and in a 3D collagen matrix. Moreover, these tumor spheroids enable assessment of the therapeutic efficacy of siRNA-based nanomedicine that demonstrates enhanced performance compared to free siRNA treatments. This platform offers a robust and scalable approach for evaluating novel nanomedicines, providing valuable insights into their therapeutic potential and underlying mechanisms of action.

Glioblastoma multiforme (GBM) is the most prevalent brain tumor that remains incurable up to now. The rapid advancement of immunotherapy makes vaccines a promising therapeutic approach for GBM. However, current vaccine platforms, such as peptides, dendritic cells, mRNA, and viral vectors, are subject to limitations such as inadequate antigen loading, insufficient immune system activation, ineffective vector delivery, complicated fabrication process, and complex formulation. Here, we developed a GBM tumor cell derived homologous exosomal nanovaccine that does not need to carry any additional tumor antigens and leads to the activation of antigen-presenting cells (APCs) in lymph nodes, increasing the proportion of immune cells (matured dendritic cells, cytotoxic T cells, and memory T cells) and in turn promoting the expression of cytokines (TNF-α, IL-6, and IFN-γ), which effectively stimulates innate immunity to trigger durable protective immunity against tumor cell insult. Our nanovaccine platform possesses efficient dual-targeting capability to lymph nodes and the brain. More importantly, the developed exosomal nanovaccines protected 100% of treated mice by inducing sustained and strong immunity against GL261-luc GBM tumor cells, resulting in 100% mouse survival (8/8) up to 5 months. Our nanovaccines also induced antitumor immune responses in the immunosuppressed CT2A-luc GBM mouse model with greatly improved survival compared to control mice. Exosomal nanovaccines also demonstrated effectiveness in preventing brain metastasis in the B16F10-luc melanoma malignant brain metastasis mouse model, and the mice showed notably improved survival rates. Our simple and potent exosomes offer a versatile platform for clinical translation as individualized vaccine therapy.

Glioblastoma (GBM) stands as the most fatal brain tumor due to limited therapeutic options and high rates of drug resistance. Current surgical and pharmacological interventions usually fail to eradicate the aggressive GBM stem cells (GSCs), which leads to the deadly GBM occurrence. Although proteolysis-targeting chimeras (PROTACs) are prosperous in drug development for tumors, their application in GBM, particularly for GSC-sensitive drug candidates remains in its nascent stages. In this regard, we designed a monoacylglycerol lipase (MAGL) targeting PROTAC, where MAGL was identified as a novel target for GSCs in our previous study. The MAGL inhibitor JZL184 was redesigned by leveraging computational chemistry analysis, and an active unit was engaged for conjugation. E3 ligand for MAGL targeted warhead conjugation was screened with bioinformatics analyses, which revealed heightened activity of the E3 ligase MDM2 in GBM, a classic negative regulator of the tumor suppressor P53, which correlates with patient prognosis. Then the PROTAC was conjugated with JZL184 analog and the MDM2 inhibitor Nutlin-3 analog. Experimental results validated that the designed JN-PROTAC effectively induced MAGL targeted degradation and concomitantly enhanced P53 activation via MDM2 inhibition and is capable of inhibiting the progression of patient-derived GSCs in vivo. This work presents a proof-of-concept PROTAC design tailored for GSCs, potentially addressing the occurrence challenges for GBM.

Despite the increasing global prevalence of neurological disorders, the development of nanoparticle (NP) technologies for brain-targeted therapies confronts considerable challenges. One of the key obstacles in treating brain diseases is the blood-brain barrier (BBB), which restricts the penetration of NP-based therapies into the brain. To address this issue, NPs can be installed with specific ligands or bioengineered to boost their precision and efficacy in targeting brain-diseased cells by navigating across the BBB, ultimately improving patient treatment outcomes. At the outset of this review, we highlighted the critical role of ligand-functionalized or bioengineered NPs in treating brain diseases from a clinical perspective. We then identified the key obstacles and challenges NPs encounter during brain delivery, including immune clearance, capture by the reticuloendothelial system (RES), the BBB, and the complex post-BBB microenvironment. Following this, we overviewed the recent progress in NPs engineering, focusing on ligand-functionalization or bionic designs to enable active BBB transcytosis and targeted delivery to brain-diseased cells. Lastly, we summarized the critical challenges hindering clinical translation, including scalability issues and off-target effects, while outlining future opportunities for designing cutting-edge brain delivery technologies.

Glioblastoma is the most common and devastating brain tumor owing to its high invasiveness and high-frequency drug resistance. Near infrared-II (NIR-II) imaging-guided phototherapy based on polymer luminogens provides a promising remedy against drug-resistant glioma, but it is difficult to maximize photoenergy utilization. Herein, we designed a series of semiconducting polymers to boost the visualization and ablation of glioblastoma. By subtly engineering the side chains or substituents on the phenothiazine and thiophene moieties, an NIR-II polymer luminogen with high-quality fluorescence performance, good solubility, superior photothermal conversion, and balanced reactive oxygen species generation is achieved. The optimal polymer possesses a branched alkyl chain and tetraphenylethylene pendant to manipulate the equilibrium between the radiative and nonradiative energy-dissipating channels. High-sensitivity NIR-II imaging was used to monitor the blood-brain barrier penetration and glioma cell targeting of apolipoprotein E-modified polymer nanoparticles. The NIR irradiation triggers and maximizes the photon utilization in prominent photodynamic/photothermal synergistic therapy in orthotopic drug-resistant glioblastoma.

Since the approval of Doxorubicin Liposomal (Doxil®) by the U.S. Food and Drug Administration (FDA) in 1995, the field of nanomedicine has undergone substantial growth, transforming the landscape of drug delivery. Nanomedicine offers innovative approaches to enhance the pharmacokinetics and pharmacodynamics of conventional therapeutic agents. Notably, nanomedicine facilitates targeted and multifunctional drug delivery as well as enabling at-site controlled drug release, improving therapeutic precision and minimizing off-target effects. To date, over 50 nanomedicines have received regulatory approval for the treatment of various diseases, with more than 100 currently undergoing clinical trials. However, despite these great advancements, the application of nanomedicines in treating brain diseases remains limited. The blood-brain barrier (BBB) hurdle and the intricate complexity of the central nervous system (CNS) significantly hinder the development of brain-targeted nanotherapeutics. In this review, we will summarize the current challenges encountered in developing nanomedicines for brain diseases and explore potential strategies to overcome these barriers, aiming to accelerate their translation into clinical practice.

Glioblastoma multiforme (GBM) is considered as one of the most lethal malignancies in the central neuron system (CNS). Despite significant advances in immunotherapy approaches for multiple tumors, the highly immunosuppressive tumor microenvironment (TME) of GBM presents critical challenges. Inspired by tumor-derived exosomes, which carry a range of tumor-associated antigens and possess improved blood-brain barrier (BBB) transcytosis, we have developed CpG adjuvant-functionalized GBM tumor-derived exosomes (Exo-CpG) to inhibit GBM proliferation and elicit long-lasting protective immunity via potent stimulation of the body's innate immunity. Our exosomal nanoplatform efficiently activates the antigen-presenting dendritic cells (DCs) in lymph nodes, promoting their maturation, and generating a strong T cell response. In combination with the anti-programmed cell death ligand-1 antibody (aPD-L1), these exosomes effectively restrain the growth of GBM in orthotopic primary GL261 and phosphatase and tensin homologue (PTEN)-deficient immunosuppressive CT2A models in immune-competent mice, significantly prolonging survival by effectively suppressing GBM recurrence. This fully natural exosomal nanoplatform offers a promising strategy for targeting the immunosuppressive TME of orthotopic primary GBM and its recurrences.