Charge-reversal nanoparticles (NPs) have the potential to enhance tumor penetration, but conventional tumor microenvironment-dependent reversal strategies suffer from low selectivity, slowness, and heterogeneity-impaired efficiency. Here, we discovered that coumarin-derived carbamate (CDC) exhibits ultrasound (US) responsiveness, enabling amino group exposure upon irradiation by a physiotherapeutic US apparatus. We then engineered US-triggered charge-reversal NPs using a polyamino acid scaffold with anionic carboxylate side chains, functionalized with CDC and loaded with therapeutic agents. Our NPs exhibited concentration- and pH-dependent rapid charge reversal , enabling zeta potential reversal from negative to positive values within 5 min at pH 6.8 via US-triggered amino group exposure. With US irradiation, the NPs achieved 3.0-fold deeper penetration and 341-fold enhanced cytotoxicity in 3D tumor spheroid models. As surface charge transitions from negative to positive, the primary endocytic pathway of the NPs shifted from macropinocytosis to caveolin-mediated endocytosis, which in turn promoted Golgi-dependent iterative transcytosis, thereby boosting intratumoral penetration. In the in vivo 4T1 murine breast cancer model, the NPs plus US elicited 93% tumor growth inhibition without detectable systemic toxicity. This approach employs US to achieve spatiotemporal control of chemical reactions, enabling efficient and rapid charge reversal and offering a strategy to enhance NP penetration into tumors.

Spatiotemporally controlled, tumor-selective activation of N-oxide prodrugs within tumors remains a longstanding challenge in cancer therapy. Herein, we report a broadly applicable strategy driven by clinical ultrasound for the reductive deoxygenation of N-oxides, enabling externally controlled prodrug activation via a riboflavin tetrabutyrate (TBR)/NADPH redox-relay system. Under mild, clinically translatable ultrasound (1 MHz, 2.0 W/cm2, 50% duty cycle), this platform promotes efficient N-O bond cleavage through single-electron transfer and hydrogen-atom transfer. Density functional theory calculations support that all ground-state steps are thermodynamically favorable with negative Gibbs free-energy changes (ΔG), supporting the feasibility of sonochemical N-oxide reduction. This method exhibits broad substrate generality toward diverse N-oxide compounds, including the clinically investigated hypoxia-activated prodrug banoxantrone (AQ4N), quinoline N-oxide, 8-hydroxyquinoline N-oxide, clozapine N-oxide, and olanzapine N-oxide. In hypoxic tumor cells, the ultrasound/TBR system enhances intracellular AQ4 formation significantly and reduces the IC50 of AQ4N from 35.0 to 2.8 mg/L. In vivo, the combination of AQ4N, TBR, and ultrasound increased intratumoral AQ4 formation by approximately 24.1-fold and achieved a tumor inhibition rate of 113.7%, outperforming AQ4N monotherapy (82.3%). This sonochemically triggered activation platform bypasses the heterogeneity of tumor-microenvironment stimuli and offers a versatile, externally controlled framework for precision prodrug chemotherapy with deep tissue penetration and clinical translatability.

Enhancing tumor selectivity remains a central challenge in cancer therapy, particularly for solid tumors with high heterogeneity. Herein, we report a novel drug delivery strategy that exploits the physiological cascade induced by tumor vascular disruption via vascular disrupting agents (VDAs) or surgery to create a transient therapeutic window characterized by local fibrin deposition and exacerbated hypoxia. We designed a dual-targeting nanoprodrug (FT11-AExT-NPs) consisting of a fibrin-binding FT11 peptide, a hypoxia-activated azo-linker, and the topoisomerase I inhibitor exatecan (ExT). This nanoprodrug selectively accumulates in tumors via fibrin targeting and releases active ExT specifically under hypoxic conditions. Using a triple-negative breast cancer 4T1 mouse model, we demonstrate that combination therapy with VDA and FT11-AExT-NPs increases the concentration of activated ExT in tumors by 31.7-fold compared to free prodrug, achieving 98.0% tumor suppression and a 66.7% cure rate. In a postoperative adjuvant setting, FT11-AExT-NPs leverages surgery-induced vascular disruption to reduce tumor recurrence by 50% through targeted eradication of residual tumor tissue. This strategy reduces reliance on tumor-specific biomarkers by exploiting treatment-induced fibrin deposition and hypoxia, and showed reduced systemic toxicity in the models tested.

Nitric oxide (NO) can effectively combat periodontitis by disrupting biofilms and suppressing inflammation; however, its clinical translation has been limited by the lack of a controllable delivery strategy. This study aimed to develop an ultrasound-controlled NO delivery platform based on a clinically approved NO donor for precise periodontitis treatment. A clinically approved NO donor, isosorbide dinitrate (ISDN), was identified that can be efficiently activated by low-intensity ultrasound (2 W/cm2) in the presence of vitamin B2 tetrabutyrate (TBR) by generating ·OH free radicals, thereby releasing NO in an on-demand and spatiotemporally controlled manner. Thereafter, ISDN-loaded nanoparticles were synthesized, and a miniaturized intraoral ultrasonic transducer for localized NO generation was developed. The reaction between NO and the reactive oxygen species (ROS) produced from TBR formed peroxynitrite, which exerted strong antibacterial and anti-biofilm effects (the bacterial survival rate within the biofilm during the formation stage was less than 10%) and inhibited NLRP3-mediated inflammation. In a rat model of periodontitis, the treatment significantly decreased bacterial load and mitigated inflammation, resulting in a reduction of inflammatory gene expression by approximately 2.4-fold, while maintaining the integrity of alveolar bone structure. Overall, this study presents a highly promising clinical application for ultrasound-controlled NO delivery strategy for precision therapy of periodontitis.

Toll-like receptor (TLR) agonists are promising for in situ tumor vaccination but suffer from poor tumor selectivity and systemic toxicity. Here, we establish a sonochemical activation strategy using a vitamin B2-derived sonosensitizer for spatiotemporally controlled immunotherapy. Riboflavin tetrabutyrate (TBR) was identified as an efficient sonosensitizer for thioketal (TK) cleavage under low-intensity ultrasound (US) and coformulated with a TK-masked TLR7/8 agonist (R848) to construct sonosensitive nanoparticles (R848/TBR NPs). Upon US irradiation, TBR generated singlet oxygen to induce immunogenic cell death and trigger R848 release through an oxidation-hydrolysis pathway, resulting in a 6.0-fold increase in intratumoral active R848. The activated in situ vaccine elicited robust antitumor immunity with >150-fold enhancement of tumor-specific T-cell responses, achieving tumor inhibition rates of 98.1% in CT26 and 95.7% in highly metastatic 4T1 models while markedly suppressing metastasis and recurrence. This work establishes a mechanistically defined and biocompatible sonochemical framework for controllable drug activation and cancer immunotherapy.

Antibody-decorated nanomedicines can selectively deliver drugs to tumors. However, their targeting efficiency diminishes as the density of the target antigen decreases. To address this limitation, this study developed a PDL1-driven, self-sustaining feedback drug-homing nanoparticle, termed aPDL1-PLG-DOX nanoparticles (aPDL1-P-DOX). This construction was prepared by loading doxorubicin (DOX) into a phenylboronic acid-bearing poly(L-glutamic acid) carrier responsive to reactive oxygen species (ROS) through boron-nitrogen coordination, followed by conjugation with an anti-PDL1 monoclonal antibody (aPDL1). The aPDL1 moiety directs nanoparticles to PDL1-expressing tumors, where elevated ROS levels trigger DOX release. In turn, residual tumor cells upregulate PDL1 expression in response to DOX, thereby enhancing subsequent recruitment of aPDL1-P-DOX and establishing a self-sustaining tumor-selective drug delivery cycle. This feedback-induced mechanism not only increases the specificity and persistence of DOX accumulation in tumors but also leverages co-delivered aPDL1 to mitigate DOX-associated immunosuppression and restore immune homeostasis. In a murine colon cancer model, this strategy achieved 98.7% inhibition of tumor growth and significantly prolonged survival, representing a promising approach for durable and precise cancer therapy.

Small-molecule drugs remain the mainstay of cancer therapy but are frequently compromised by poor tumor selectivity and dose-limiting systemic toxicity. Prodrug strategies have therefore been widely developed to improve therapeutic indices; however, conventional prodrugs that rely on endogenous biological stimuli often suffer from interpatient heterogeneity and unintended off-target activation. In this context, ultrasound (US) has emerged as a highly attractive exogenous trigger for on-demand prodrug activation owing to its excellent safety profile, deep tissue penetration, and precise spatiotemporal controllability. In this review, we provide a comprehensive and systematic overview of US-activated prodrugs for cancer therapy. We first summarize the fundamental physical principles of US and delineate four major US-induced effectsmechanical, cavitation, thermal, and chemicalhighlighting how each effect can induce specific chemical bond cleavage and drug release. Particular emphasis is placed on the rapidly advancing field of sonochemistry, especially sonosensitizer-mediated electron transfer and reactive oxygen species/radical generation, which enables highly efficient and controllable chemical activation of prodrugs under clinically relevant US conditions. By critically comparing activation mechanisms, chemical design strategies, and representative prodrug systems, this review clarifies the unique advantages and limitations of different US-responsive approaches. Importantly, we highlight recent advances that demonstrate the superiority of sonochemical activation in achieving precise, deep-tissue, and minimally invasive drug activation. Collectively, this work aims to provide conceptual and practical guidance for the rational design of next-generation US-activated prodrugs and to accelerate their translation toward safer and more effective precision cancer therapies.

The selective eradication of cancer cells remains a primary objective in tumor therapy. To this end, tumor-targeted therapy has emerged as a key strategy to enhance drug efficacy and reduce systemic toxicity. Herein, we developed an in situ covalent targeted prodrug system that contains a coagulation targeting peptide modified nanoparticle (AMINP) and ultrasound irradiation. In this system, ultrasound-guided localized vascular disruption induces in situ generation of fibrin and the activated coagulation factor XIII (FXIIIa) within tumors. FXIIIa catalyzes the covalent crosslinking of AMINP with fibrin, enabling exceptional tumor targeting. This system is spatiotemporally controllable, relying on ultrasound to create binding targets and enhance hypoxic conditions for prodrug activation. Combined with ultrasound, AMINP achieved highly efficient tumor enrichment, increasing active drug concentration 52.1-fold versus controls and achieving 98.9% tumor suppression, with no recurrence observed in rechallenge experiments. This system establishes a robust and promising method for precision drug delivery.

Controlled nitric oxide (NO) release within deep periodontal pockets remains a critical unmet need for effective periodontitis therapy, as conventional approaches are plagued by poor targeting, uncontrolled release, and limited deep-tissue penetration. Herein, we engineer sonosensitized hemoglobin nanoparticles (PH-SNO) using heme as an endogenous sonosensitizer and S-nitrosothiol (SNO) as a robust NO donor, enabling ultrasound (US)-mediated synergistic gas-sonodynamic therapy for periodontitis. Upon US irradiation, PH-SNO simultaneously generates reactive oxygen species (ROS) via heme and triggers S-NO bond cleavage for on-demand NO release; ROS and NO further react to form peroxynitrite, exerting potent oxidative-nitrosative stress. This dual effect eradicates major periodontal pathogens, disrupts biofilms, abrogates NF-κB signaling and NLRP3 inflammasome activation, and downregulates pro-inflammatory cytokines. In vivo studies confirm that PH-SNO/US alleviates gingival inflammation, suppresses osteoclast activity, preserves alveolar bone, and promotes tissue repair with excellent biocompatibility, providing a safe, noninvasive, and translatable nonantibiotic therapeutic strategy for periodontitis.

Bone defects remain a major clinical challenge due to the slow rate of recovery, complex surgical procedures, and great impact on the lives of patients. Therefore, the development of biocompatible, durable, degradable artificial bone grafts is highly desirable. Inspired by the natural composition of human bone, this study reports the fabrication of poly(lactic acid) (PLA)/zinc-doped hydroxyapatite (Zn-HA) composite materials via the melt blending method. The chemical properties, mechanical performance, degradability, and biocompatibility of the composites were evaluated systematically. Among them, the 10 wt

Intracerebral hemorrhage (ICH) is a life-threatening cerebrovascular disorder characterized by rapid hematoma expansion and secondary neurovascular injury, resulting in high mortality and disability. Current hemostatic drugs lack lesion selectivity and fail to stabilize fragile vasculature, leaving patients vulnerable to secondary rebleeding. To address these limitations, we developed ATHEMO (Active-Targeted HEmostasis and brain Microenvironment Optimizer), a peptide-modified nanoplatform designed for targeted hemostasis and sustained neuroprotection. Incorporating a von Willebrand factor (vWF)-binding sequence, ATHEMO precisely homes to ruptured vessels, where it establishes a stable adhesive interface that halts active bleeding and reinforces vascular integrity. Concurrently, the nanocarrier provides controlled release of quercetin, effectively mitigating oxidative stress, promoting M2-type microglial polarization, and preserving blood-brain barrier function. In a murine ICH model, ATHEMO reduced hematoma volume by nearly 70 %, alleviated cerebral edema, improved perfusion, and restored both cognitive and motor functions during long-term recovery. Transcriptomic profiling revealed downregulation of inflammatory cascades and enhancement of synaptic signaling, underscoring ATHEMO's dual hemostatic and neuroprotective effects. These findings demonstrate that combining targeted bleeding control with microenvironment regulation offers a precision nanotherapeutic strategy for ICH, potentially translatable to other non-compressible hemorrhagic conditions.

The development of immune checkpoint inhibitors, especially PDL1 antibodies, has revolutionized cancer therapy, but the posttherapy recycling of PDL1 proteins poses a significant challenge by inducing resistance and reducing treatment efficacy. To address this, we introduce an integrin-driven, lysosome-targeted nanochimera, composed of poly(glutamic acid), RGD peptides, and PDL1 antibodies, is designed to engage the target PDL1 protein, with the αvβ3 integrin binding to the multivalent RGD peptides to direct the complex through the endocytosomal pathway to the lysosome, ensuring PDL1 degradation and blocking its recycling. Our in vitro and in vivo experiments demonstrate that these nanochimeras potently activate T-cell antitumor immunity by downregulating PDL1 expression within tumor cells and tissues, significantly enhancing the efficacy of PDL1 antibodies. A key discovery of our study is the pivotal role of multivalent RGD peptides in facilitating target protein degradation, providing valuable insights for the development of more efficacious and sophisticated immunotherapies.

Selective prodrug activation at tumor sites through noninvasive external stimuli represents a promising strategy in enhancing the therapeutic index. Here, we report a p-azidobenzyloxycarbonyl (PAzBC)-based prodrug platform activated by physiotherapy-grade ultrasound (2.0 W/cm2, 1 MHz) through radical-mediated cascade elimination. Mechanistic studies reveal that ultrasound initiates single-electron-transfer (SET) and hydrogen-atom-transfer (HAT) processes, enabling efficient azide-to-amine reduction. This activation is further amplified by superoxide anion radicals generated via acoustic sensitizers, as confirmed by DFT calculations and radical trapping experiments. The PAzBC platform demonstrates broad applicability with diverse drug functionalities (amino, hydroxyl, sulfhydryl), achieving >99% azide reduction efficiency and approximately 40% active drug release under optimized sonication conditions. Cellular studies reveal a 4.1-115.5-fold reduction in prodrug toxicity and a 11.9-169.5-fold enhancement in selective activation, highlighting its potential for clinical translation. This work establishes a robust platform for spatiotemporally controlled drug delivery, advancing the field of ultrasound-mediated precision cancer therapy.

Immunotherapy has emerged as an important approach for cancer treatment. However, most drugs for activating the cancer-immunity cycle have serious side effects from systemic off-target action, endangering patients' safety. Prodrug-loaded nanoparticles integrate prodrug activation strategies based on passive or active targeted delivery, which is expected to improve the enrichment of drugs in tumors, reduce the activation of drugs in normal tissues, and enhance the drugs' tumor selectivity. For example, adjuvants represented by Toll-like receptor 7/8 (TLR7/8) agonists and stimulator of interferon genes (STING) agonists are promising for the de novo priming of antitumor immunity. However, these drugs face pressing challenges in achieving tumor-specific immune activation to enhance the therapeutic effect and minimize systemic toxicity. This review systematically analyzes recent advances in these prodrug-loaded nanoparticles for precise controlled release adjuvants in tumors, focusing on TLR7/8 and STING agonists. We discuss the tumor microenvironment-driven prodrug activation, externally triggered prodrug activation, and explore the generalized design principles and mechanisms applicable to prodrug-loaded nanoparticles. Furthermore, we explore these adjuvants' current status, challenges, and future development direction in the clinical translation. This article aims to inspire the further development of these agonists. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

ObjectiveTo develop a novel polyamino acid-based nanohydrogel drug delivery system for dexamethasone to enhance its delivery efficiency to the inner ear.MethodsA fluorescein-labeled polyglutamic acid-based polyamino acid dexamethasone nanohydrogel was synthesized, and its gelation time was measured. The hydrogel was surgically injected into the round window niche of guinea pigs to determine its degradation time in the middle ear cavity in vivo. The safety, pharmacokinetics, and distribution patterns of dexamethasone in the inner ear were evaluated.ResultsThe hydrogel exhibited a gelation time of 80 seconds in a 37℃ water bath. In vivo, the hydrogel was almost completely degraded within 7 days in the middle ear cavity of guinea pigs. Transient hearing loss was observed one day after administration, but hearing gradually returned to normal over time. No significant cytotoxicity, vestibular stimulation signs, or pathological abnormalities in spiral ganglion cells were observed. Histopathological examination revealed no significant inflammatory reactions. Pharmacokinetic analysis demonstrated sustained drug release and prolonged dexamethasone activity. Immunofluorescence staining confirmed the distribution of dexamethasone in both the cochlea and vestibular organs.ConclusionThe polyamino acid nanohydrogel exhibits excellent injectability and biodegradability, representing a safe and effective drug delivery system for the inner ear.

Breakthrough advances in nanotechnology have substantially enhanced lymph node (LN) targeting efficiency and immune cell uptake of nanovaccines, establishing novel avenues for tumor immunotherapy. Nevertheless, current nanovaccines predominantly accumulate in subcapsular sinuses (SCS) or superficial cortical regions post-lymphatic transport, failing to traverse anatomical barriers to reach the T cell-enriched paracortex-a critical delivery bottleneck that severely limits full activation of cellular immunity. Furthermore, the absence of tumor-specific endogenous stimuli in LN microenvironments invalidates conventional environment-responsive delivery strategies. Herein, "dynamically size-change nanovaccine" (DashVax), a time-controlled self-disassembling nanovaccine is presented that achieves dynamic size transition from 102 to 5 nm via physiologically regulated imine bond hydrolysis. This design capitalizes on the lymphatic drainage superiority of large particles and tissue-penetrating capacity of small units, achieving a breakthrough 7.3-fold enhancement in paracortical antigen delivery compared to non-size-change nanovaccines (NoncVax). DashVax demonstrates robust antigen-specific immune responses and tumor growth suppression in both B16-OVA and MC38 tumor models. This exogenous stimulus-free temporal delivery strategy not only redefines nanovaccine design principles but also elucidates fundamental correlations between intranodal delivery kinetics and immune activation efficacy.

Polymers are widely used as mRNA delivery platforms, but their clinical translation is limited by challenges such as nonorgan-selective expression and low in vivo efficacy. Poly(amino acids), particularly poly(aspartic acid) (PAsp), have been extensively studied for drug, nucleic acid, and protein delivery due to their excellent biodegradability and biocompatibility. However, the role of aminolysis-modified PAsp in mRNA delivery remains to be fully explored. In this study, we developed a series of polyamine-aminolyzed PAsp derivatives (P-An), further functionalized with heterocyclic small molecules (P-An-M), and evaluated their in vitro and in vivo mRNA transfection efficiency. We synthesized 24 polymers and identified three N,N '-bis(3-aminopropyl)ethylenediamine (PDA)-modified PAsp derivatives that efficiently transfected Luc-mRNA in 293T cells: P-PDA, P-PDA-I, and P-PDA-BI (where I and BI represent 1H-imidazole-4-carboxylic acid and 1H-benzimidazole-4-carboxylic acid, respectively). In vivo experiments demonstrated that P-PDA, P-PDA-I, and P-PDA-BI selectively delivered mRNA to the lungs and achieved a significant level of protein expression. This work provides a promising strategy for developing polymer-based materials for mRNA lung therapy, with potential applications in treating pulmonary diseases.

In recent years, the use of nanotechnologies to improve immunotherapy efficiency has attracted increasing interest in preventive and therapeutic cancer vaccine design. However, current nanocarriers are restricted by difficulties in the systematic spatial coordinative transport of antigens, which greatly hampers the immune response efficacy of nanovaccines. Herein, we designed a mannan-decorated stimulator of the interferon genes (STING)-activating vaccine carrier for spatial coordinative stimulation of antigen-specific immune responses and elicitation of robust antitumor immunity. Mannan-decoration as the shell could significantly enhance the lymph node draining ability of the nanovaccines, especially in CD8+ dendritic cells (DCs). Azole molecule end-capped polylactic acid-polyethylenimine (PLA-PEI-4BImi) with innate stimulating activity was applied as the inner core for coordinating antigen-presenting cell activation and antigen cross-presentation. In the in vivo therapy study, single usage of this nanovaccine could achieve a 93% tumor suppression rate in the B16-OVA tumor model, which is superior to the commercialized aluminum adjuvant. This study demonstrates that a rational design of vaccine carriers for solving spatial transmission issues could greatly improve cancer vaccine efficiencies.

Drug therapy, including chemotherapy and immunotherapy, remains a cornerstone of cancer treatment; however, significant toxic side effects are often unavoidable, inhibiting tumor growth while causing damage to multiple organ systems. Polymeric nanomedicines have shown substantial promise in addressing the limitations of small-molecule drugs, such as poor solubility, rapid clearance, low tumor retention, and adverse effects, thereby enhancing the therapeutic index. Despite these advances, clinical outcomes indicate that the overall survival rates of cancer patients post-treatment are often not significantly higher than those achieved with standard small-molecule drugs. This is largely due to the inadequate tumor targeting and limited tumor penetration of polymeric drugs despite their drug release and targeting capabilities. While actively tumor-targeted and selectively activated drug strategies can potentially improve drug targeting, traditional approaches have yielded unsatisfactory results due to insufficient differences in targets, such as markers and stimuli, between tumor and normal tissues. Recent innovations focus on utilizing drug or external stimuli, such as light, radiation, and ultrasound, to amplify tumor-associated markers or stimuli, enabling more precise tumor targeting and selective drug activation. Based on these innovations, actively targeted or selectively activated polymeric nanomedicines can further enhance drug accumulation within tumors and improve therapeutic outcomes. Moreover, the integration of actively tumor-targeting and tumor-selectively activated strategies represents a significant advancement, which achieves simultaneously enhanced drug accumulation and selective activation within the tumors. This review highlights the significant potential, challenges, and advanced strategies of polymeric nanomedicines in targeted tumor therapy, emphasizing the need for ongoing research to optimize their effectiveness and ultimately improve patient outcomes, paving the way for more effective and less toxic cancer treatment options.