Exosomes (30–150 nm EVs) constitute a mobile communication layer that links tumor, stromal and immune niches. Importantly, immune escape can be encoded at the EV-sorting step: Munc13–4 promotes preferential PD-L1 loading into exosomes, and disrupting this pathway restores CD8⁺ function and improves checkpoint responsiveness in vivo (27). EVs can also impose exhaustion programs without direct tumor–T-cell contact; breast cancer EVs promote CD8⁺ exhaustion via TGF-β type II receptor signaling (28).

Beyond direct immune targeting, tumor exosomal tsRNA can induce fibroblast senescence and Galectin-9 secretion, amplifying tolerance through stromal reprogramming (29). Design implication: EV biology provides both (i) targets to neutralize EV-mediated suppression (e.g., EV PD-L1/decoy pathways) and (ii) templates for niche-local delivery when fused with programmable cores.

Tumor-derived exosomes (TEX) do not merely reflect suppression; they can actively amplify it and create resistance modes that classic dosing does not fully address. Exosomal PD-L1 can reinforce a Treg-M2 macrophage positive feedback loop (30), and TEX can blunt ICIs through antibody decoying that reduces functional drug availability at immune synapses (31). TEX also program innate dominance: exosomal miR-205 can drive M2 polarization via PTEN/PI3K–AKT–mTOR in ovarian cancer (32), and additional miRNA transfer routes sustain macrophage re-education in other tumor contexts (33). In parallel, TEX can expand suppressive pools by recruiting MDSCs via CXCR4 upregulation through TLR2/NF-κB signaling (34), remodel immune entry rules by reprogramming lymphatic endothelial cells toward IDO-linked tolerance (35), and even delete effector function directly; patient plasma small EVs can induce intrinsic apoptosis in activated T cells (36). These observations together motivate hybrid exo-nanomaterial solutions that combine EV-like trafficking and biocompatibility with programmable payload control, aiming to neutralize EV-mediated resistance (e.g., decoys), reprogram suppressive myeloid and stromal compartments, and protect effector function.

Conversely, immune-cell–derived EVs and EV vaccination strategies provide constructive “design blueprints” for therapeutic engineering. Circulating NK-cell exosomes can exhibit antitumoral activity in patient-derived settings (37), and cytokine conditioning can enhance NK-exosome cytotoxic loading and killing potency (38), implying that EV function can be tuned via controllable input rules. DC-derived EVs can be engineered to co-present IL-12 and an anti-CTLA-4 format on their surface to strengthen CD8⁺ activation (39), while CAR-T-derived EVs can retain antigen specificity and contribute directly to antineoplastic effects (40) with reports of potent activity and lower systemic toxicity than whole-cell approaches (41). Finally, in vivo EV vaccination that routes antigens into EV production pathways can elicit strong tumor-specific CD8⁺ immunity and near-complete tumor control in stringent dual-antigen models, underscoring how EV biology can be repurposed as a priming factory to address antigen presentation bottlenecks (42).

Rather than cataloging exo-nanomaterials by material class, we use an “immune-by-design” mapping that connects TIME barriers to engineering levers, intended immunological effects, and minimal in vivo readouts. This rubric links physicochemical and pharmaceutic parameters (size/charge/shape, membrane source, surface ligands, stimulus-responsiveness, co-delivery and release kinetics, and administration route) to concrete bottlenecks (spatial exclusion, suppressive myeloid circuits, impaired antigen presentation, and systemic toxicity) and specifies what constitutes adequate in vivo evidence for TIME remodeling. Table 1 is used as the organizing scaffold and evaluation yardstick throughout Sections 3–5, enabling side-by-side comparison of systems by barrier targeted, design logic, mechanistic readouts, and translational trade-offs, rather than by materials taxonomy.

A core limitation of many immunotherapies is that only a small fraction of the injected agent reaches tumors or the correct immune cell compartments. Nanomaterials increase this “on-target rate” by stabilizing fragile cargos, prolonging circulation and enabling both lymphoid trafficking and tumor deposition. Antigen-capturing nanoparticles (AC-NPs) that scavenge therapy-released tumor antigens and ferry them into cross-presenting DCs, related biomimetic nanovaccines cloaking immunogenic polymer cores with tumor membranes to broaden the antigen repertoire and preserve native epitope conformation, and intratumoral STING-activating nanovaccines built on synthetic polymer adjuvants that more effectively reprogram draining lymph nodes and the local TIME than systemic dosing collectively exemplify how nanodelivery can script the location and quality of immune activation rather than simply raise drug concentration (43–45).

A second thrust is to design nanomaterials that directly engage innate immune pathways such as STING, TLR7/8 and cGAS-related sensors or that deliver these agonists into the cytosol with controlled kinetics. Polyvalent PC7A-based polymeric nanoparticles show how material properties can encode signal duration: by undergoing immune-dependent phase transitions they prolong STING activation and type-I IFN programs, with polymer architecture rather than dose alone dictating the temporal profile (46). Nanoparticles that encapsulate cyclic dinucleotide agonists in polymersome shells build on this logic, markedly improving pharmacokinetics, shifting biodistribution toward tumors and thereby opening an intravenous therapeutic window for systemic STING immunotherapy and checkpoint combinations (47). Chemically programmed STING-activating nano-liposomes (SAProsomes), in which agonists are covalently embedded in the liposomal membrane, further coordinate release and reduce systemic inflammation while maintaining strong intratumoral interferon responses (48).

Innate agonists can also be positioned in space using physical targeting and hybrid materials. Nucleotide nanocomplexes displayed on ultrasound microbubbles enable image-guided vascular extravasation and local cytosolic delivery of cGAMP, sharply enhancing STING activation in otherwise poorly penetrant tumors (49). Dual-STING-activating nanosystems such as D-SAM integrate direct receptor agonism with amplified intracellular trafficking, broadening the fraction of tumors that respond and helping to overcome resistance to checkpoint blockade in preclinical models (50). Hybrid manganese nanoparticles, which both debulk cancer stem cell populations and release Mn²⁺ as a cofactor for cGAS–STING signaling, couple physical tumor reduction to innate “ignition” in highly refractory carcinomas (51). Finally, implantable sandwich-structured dual-drug depots that release a non-nucleotide STING agonist first and an apoptosis inducer second create a staged local cascade particularly suited to TIME re-education after debulking surgery and to the prevention of post-surgical recurrence (52). Across these designs, nanomaterials converge on a shared logic: they enhance cytosolic access for agonists, shape the kinetics of innate signaling and localize activation to TIME niches where antigen presentation and T-cell priming are most effective.

Even with strong innate triggers, immunotherapy fails if suppressive myeloid and stromal programs remain intact, so nanomaterials are increasingly being used to edit TIME cell states directly. Albumin-based nanoparticles co-delivering the photothermal sensitizer IR820 and the SHP2 inhibitor SHP099 can reorient M2-like TAMs toward M1-like phenotypes, restore macrophage phagocytosis and reinforce cytotoxic T-cell recruitment, jointly shifting the TIME from suppressive to inflamed while limiting systemic exposure to the inhibitor (53). In hepatocellular carcinoma, lipid-coated tannic-acid nanoparticles carrying a CXCR4 antagonist (807-NPs) disrupt the hypoxia-driven CXCL12/CXCR4 axis that supports M2 polarization and T-cell exclusion, yielding marked TAM repolarization and enhanced sensitivity to PD-1 blockade (54). Polymeric micellar nanoparticles that co-formulate a TLR7/8 agonist with a PI3Kδ inhibitor extend this concept into the context of radiotherapy: by reducing MDSCs and tissue-resident Tregs while promoting type-1 macrophages and adaptive T- and B-cell expansion, they “lock” immunostimulatory and anti-suppressive cues into a single spatiotemporal package and help prevent the TIME from re-establishing resistance after irradiation (55). In each case, nanomaterials are not simply adding more stimulatory signals but actively subtracting suppressive ones within the same anatomical compartment.

Finally, different nanomaterial classes tend to produce distinct immune signatures because they differ in uptake pathways and degradation kinetics. PPS-based polymeric nanoparticles carrying TLR7/8 agonists can be tuned to selectively prolong DC activation, maintaining IL-12-dominated priming while limiting systemic cytokine spillover; adjusting their degradation rate allows innate activation windows to be aligned with antigen presentation and T-cell priming (56). By contrast, amphiphilic prodrug self-assemblies of the TLR7/8 agonist R848 form carrier-free nanostructures whose disassembly is tied to intracellular enzymatic or redox environments, creating high local receptor potency with reduced off-target stimulation and minimal excipient burden (57). In practical terms, polymeric carriers excel at programmable multi-cargo release, whereas prodrug or coordination assemblies boost per-particle immunogenicity and simplify formulations. Recognizing these class-specific tendencies provides a useful framework for rational exo-nanomaterial design in subsequent sections.

Exo-nanomaterials are hybrids that integrate natural exosomes (or exosome-like EVs) with synthetic nanomaterials into a single therapeutic unit. The logic is pragmatic: exosomes are biologically “native” carriers with low immunogenicity, long circulation, and inherent roles in immune communication, but their translation is often limited by low yield, heterogeneity, and modest cargo capacity. Scalable top-down production of exosome-mimetic nanovesicles by membrane extrusion can boost vesicle yield while preserving much of the parent-cell surface identity, helping address the manufacturing bottleneck (58). Reproducible wrapping of membranes onto cores has also been enabled by microfluidic sonication–driven fusion (59).

An overview of exo-nanomaterial engineering routes, surface design strategies and immune activation pathways is illustrated in Figure 2.

On the other side, synthetic nanomaterials bring what exosomes usually lack: high loading density, precise control over size/shape/charge, and stimulus-responsive behaviors. When fused, the exosome shell supplies “self” markers and targeting ligands, while the core supplies programmable physics. Direct membrane-fusion techniques—like microfluidic sonication—allow exosome membranes to be wrapped onto diverse nanoparticle cores without fully disrupting the vesicle architecture, which is essential for reproducible hybrid assembly.

Functionally, the hybrid often outperforms either component. For instance, brain-targeted exosome-mimetic cell membrane nanovesicles use an internal nanocore to carry therapeutic oligonucleotides, while the exosome-mimetic cloak improves blood–brain barrier penetration and glioblastoma homing, resulting in higher intratumoral drug accumulation and better survival than free oligonucleotides; similarly, integrate chemotherapeutic and photothermal agents within a vesicular shell, coupling strong photothermal/chemo capacity with immune camouflage to amplify tumor penetration and tumor cell killing (60, 61). Overall, fusion is not a cosmetic add-on; it is a strategy to co-opt biology for navigation and physics for controllable killing/immune priming.

After selecting a construction route, the choice of payload determines how a hybrid system reshapes the TIME. At the nucleic acid level, a pivotal direction is to use engineered exosomes to deliver RNA interference or gene-editing cargos. Preclinical work has already shown that exosomes engineered to deliver siRNA against mutant KRAS can achieve on-target pathway inhibition and tumor control in pancreatic cancer models, setting the conceptual stage for clinical translation (74). Building on this logic, many platforms now embed small, labile immune agonists—such as STING, TLR and cGAS–STING-axis activators—into exosomal or exosome-mimetic vesicles so that these molecules are protected during circulation, released where needed, and translated into heightened antigen presentation, elevated CXCL10 and IFN-β, and more robust CD8⁺ T-cell priming.

A complementary strategy is to exploit the membrane itself as an “active shell.” Exosomes derived from immune cells can carry intrinsic antitumor instructions through their surface receptors and cargo. Photosensitive hybrid γδ-T-cell exosomes, for example, insert a photosensitizer into γδ-T-derived vesicles so that light-triggered ROS induces immunogenic cell death, while γδ-T exosomal proteins simultaneously stimulate NK and CD8⁺ T-cell activity, producing both strong local tumor control and enhanced systemic antitumor immunity (75). Beneath these biological interfaces, metallic or oxide nano-cores can be introduced to add catalytic ROS generation, ferroptosis enhancement or photothermal conversion. When such cores are wrapped in an exosomal shell, they concentrate within tumors and “turn immune death on” without the usual off-target toxicity of free nano-agents; in this view, the inorganic core functions as a compact physical engine, whereas the exosomal surface negotiates biological access and immune dialogue.

Targeting in exo-nanomaterials works at two coupled levels. First, hybrids inherit homing from donor membranes (integrins, tetraspanins, chemokine receptors). Second, they add ligands through lipid-anchoring, click chemistry, or genetic display in parental cells. A chimeric exosome platform functionalized with STING activation for personalized glioblastoma immunotherapy shows that targeting and immune activation can be optimized together: the engineered exosomal membrane drives glioma homing, while the internal STING-activating cargo induces strong type-I IFN signaling and deep TIME reprogramming (76).

Stimulus-responsive release then decides when and where payloads unlock. Light-triggered systems are particularly mature: designer exosomes that co-deliver chemotherapeutics, gene cargos and photothermal agents can use near-infrared irradiation to induce local hyperthermia and controlled drug release, achieving efficient tumor-targeted chemo/gene/photothermal combination therapy (77). Endogenous triggers are equally important for deep lesions. Acidity-activatable dynamic hybrid nanoplatforms derived from M1 macrophage EVs remain stable in circulation but reconfigure in the acidic tumor microenvironment, boosting triple-synergistic cancer immunotherapy through checkpoint enhancement, myeloid reprogramming and effector T-cell activation (78).

Conceptually, the best hybrids orchestrate a tightly coupled cascade in which an initial stimulus leads to tumor cell killing, the release of tumor antigens, the activation of innate immune pathways and, ultimately, the expansion of adaptive antitumor responses. It is this closed immunological loop that transforms a nanomedicine into a genuine nano-immunotherapy.

A core promise of exo-nanomaterials is that they can start immunity where tumors are silent. Cold tumors typically lack strong danger signals, so DCs stay immature and T cells fail to enter or persist. Exosome-hybrid platforms address this at two levels: (i) immunogenic tumor killing that releases antigens and DAMPs, and (ii) direct adjuvant delivery to APCs.

Photo-activated hybrids are a clean example. Exosome-encapsulated black phosphorus nanoparticles act as a photothermal/photodynamic core that triggers robust ICD, while the exosomal membrane improves intratumoral delivery and antigen capture, collectively boosting DC maturation and downstream CD8⁺ priming in multiple models (79). A complementary design uses tumor-exocytosed exosome/AIE luminogen hybrid nanovesicles that achieve deep tumor penetration before light activation; this sequence (penetration → ROS-mediated tumor cell death) markedly enhances photodynamic efficacy and is expected to increase the availability of tumor antigens in situ (80).

Cold-to-hot conversion can also be achieved by engineering the adjuvant directly onto/into exosome hybrids. In a representative glioma system, immune exosomes loading self-assembled therapeutic nanomicelles traverse the blood–brain barrier; once inside the brain, the combined chemo- and immunotherapeutic effects of the payload enhance glioblastoma control and promote local immune activation within the brain tumor microenvironment (81). Beyond exosome platforms, ferroptosis-augmented sonodynamic nanoplatforms further demonstrate that carefully tuned ROS/ferroptotic death can amplify sonodynamic tumor killing and provide a ferroptosis-augmented platform that could, in principle, be combined with immunotherapy (82). Exosome-coated nanoparticles for glioblastoma exemplify how cloaking inorganic or drug-loaded cores with tissue-homing exosomal membranes can improve intratumoral accumulation and treatment specificity (83).

Even in “hotter” tumors, ICI can fail because local suppressive cues and circulating exosomal checkpoints blunt T cells. Exo-nanomaterials attack both. First, hybrids can locally remove PD-L1 pressure. Biomimetic exosomal vesicles loaded with siRNA against PD-L1 have been used to inhibit tumor secretion of PD-L1-rich exosomes, thereby reducing systemic “decoy” suppression of PD-1⁺ T cells and improving CD8⁺ T-cell–mediated antitumor responses in preclinical models (84). Second, hybrids can reprogram suppressive myeloid checkpoints that sit upstream of PD-1 failure. Engineered exosome-like nanovesicles that promote tumor ferroptosis have been shown to remodel the tumor microenvironment and drive macrophages toward a more inflammatory, antigen-presenting phenotype, thereby creating conditions that are more permissive for effective checkpoint blockade (85). Together, these data suggest that exo-nanomaterials can create “ICI-ready TIMEs” by allowing checkpoint antibodies to act on a remodeled, less suppressive target.

Exo-nanomaterials are especially well matched to vaccines because they can co-deliver antigen and adjuvant in the same lymph-node-draining particle, preserving native conformations and trafficking routes.

A clear personalized example is DC-derived exosome neoantigen nanovaccination, where exosomes loaded with neoantigenic peptide nanocomplexes drive strong CD8⁺ expansion and potent antitumor activity. The vesicular membrane promotes lymph node uptake and efficient cross-presentation compared with soluble peptides, improving primary tumor control and reducing metastatic burden in preclinical models (86). Complementarily, engineered exosome-like nanovesicles that reprogram the tumor microenvironment and promote ferroptosis provide a semi-biological vaccine-like effect: they carry tumor antigens while simultaneously modulating stromal and myeloid compartments, so that cytotoxic T lymphocytes (CTLs) attack both malignant cells and supportive stromal elements.

Most successful exo-nanomaterial regimens now behave like “built-in combination therapies.” The hybrid supplies a physical trigger and a biological traffic map, so that killing and immune priming are inseparable in practice.

Phototherapy-driven exo-hybrids described above are not just cytotoxic; they are antigen-making machines that pulse danger signals at the exact time immune cells arrive. Thermosensitive exosome–liposome hybrid nanoparticles that co-deliver docetaxel and GM-CSF provide a similar proof-of-concept: under mild hyperthermia, a single vesicular platform can combine locoregional chemotherapy with systemic chemoimmunotherapy and significantly improve control of metastatic peritoneal carcinoma over chemotherapy alone (87). Sonodynamic and ferroptosis-coupled hybrids extend this logic to deep lesions by producing ROS and immunogenic death under ultrasound, while simultaneously reshaping local redox and lipid peroxidation pathways. Mechanistically, these systems illustrate a shared rule: the tighter the stimulus–killing–APC loop, the stronger the systemic immunity.

Evidence for immunotherapy-active exo-nanomaterials is no longer confined to one niche tumor. In glioblastoma, neural stem-cell-derived exosomes delivering CpG-STAT3 antisense oligonucleotides show that re-arming local myeloid/APC populations and relieving STAT3-driven suppression can convert a poorly immunogenic glioma into an immunotherapy-responsive state (88). In hepatocellular carcinoma, exosome-like photo-immunotherapy nanomedicines demonstrate that liver-tropic vesicular properties can be paired with external light triggers to induce potent intrahepatic tumor control and to remodel the immune microenvironment toward enhanced antitumor responses (89).

In fibroblast-rich solid tumors, ferroptosis-promoting exosome-like nanovesicles highlight a distinct advantage of exosome-mimetic hybrids: by targeting both tumor cells and suppressive stromal/myeloid components, they open the stromal barrier and increase ICI accessibility. Finally, in melanoma, breast and colon models, tumor-exosome-bionic nanozymes based on Type-I AIE photosensitizers induce ICD-associated DAMP release, promote DC maturation and enhance CD8⁺ T-cell–mediated antitumor immunity (90).