As one of the leading causes of death worldwide, cancer has driven the advancement of targeted therapy toward greater precision and reduced off-target effects. Liposomes, with their biocompatibility, tunable properties, and clinical success, are among the most promising nanocarriers, yet their tumor-targeting specificity remains limited. Aptamer-functionalized liposomes provide a synergistic solution by combining selective aptamer-receptor recognition with efficient drug encapsulation, achieving enhanced tumor targeting and controlled release. Recent advances have expanded this platform toward multi-targeting, stimuli-responsive systems, and theranostic applications, thereby extending the potential of conventional liposomes. This review offers an integrated perspective on the structural design, internalization pathways, and therapeutic applications of aptamer-liposome systems across various cancers. Key barriers, including aptamer instability, scalable conjugation, and limited clinical translation, are critically discussed, alongside emerging strategies to address them. The convergence of aptamer targeting and liposomal delivery represents a transformative step toward next-generation nanotherapeutics, offering a paradigm shift in precision oncology by enabling personalized, selective, and multifunctional cancer therapy.

The combination of photodynamic therapy (PDT) and chemotherapy is a promising strategy to improve the effect of tumor treatment. However, the existing construction systems have insufficient killing selectivity and unclear synergistic mechanism. Herein, we developed a novel anticancer strategy based on a hypoxia-activated molecular prodrug (Cy-NM), which was formed by the covalent connection of an alkylating agent (NM) and a photodynamic photosensitizer (Cy-NH2), to achieve cooperative precision photodynamic-chemotherapy. Cy-NM with positive charge could structure-inherent targeting (SIT) to tumors and localized to the mitochondria of cancer cells. Under the action of azo reductase, Cy-NM was converted into Cy-NH2, thereby enhancing the photodynamic effect through the intramolecular charge transfer (ICT) effect and releasing NM. PDT consumed oxygen to further exacerbate tumor hypoxia and promote drug release, while the released drugs enhanced the photodynamic damage to mitochondria. The two treatments exhibited a synergistic promotion effect, achieving more effective and selective in killing cancer cells. Moreover, the fluorescence of Cy-NM changed from “off” to “on” after activation, which realized precise fluorescence diagnosis and visual treatment of tumors. Therefore, this prodrug design strategy offers a new perspective for improving the accuracy and efficiency of tumor treatment.

Long-term tumor immunotherapy remains challenging due to poor drug retention and immune activation. Here, we proposed a chitosan-based composite hydrogel capable of in situ gelation at physiological temperature to form a durable depot for sustained and tumor microenvironment (TME)-responsive release. The system integrated indocyanine green (ICG)-loaded gold nanorods within boronic acid-modified mesoporous silica (GSB) and thermoresponsive nanocomposites (ICG@GAN), which were further loaded with β-glycerophosphate (β-GP) and genipin and embedded in a carboxymethyl chitosan matrix. Upon injection, sequential release of β-GP and genipin triggered rapid physical and stable chemical cross-linking, forming a high-strength double-network hydrogel. Gradual leaching of β-GP, along with enzymatic degradation of chitosan, sustained the release of ICG@GAN. In the TME, cleavage of boronate esters triggered the release of ICG and GSB, enabling synergistic photothermal and ROS-mediated tumor cell apoptosis and tumor-associated macrophage repolarization. Meanwhile, chitosan modulated the immune feedback to amplify immune activation and infiltration. This integrated hydrogel platform markedly suppressed tumor growth and metastasis, offering a promising strategy for long-term immunotherapy.

Microneedles (MNs), as a transdermal drug delivery system, not only exhibit superior therapeutic efficacy but also ensure drug stability, holding remarkable advantages over conventional oral or intravenous administration routes. Recent advances in next-generation smart-responsive MN systems have focused on boosting real-time biomedical applicability through the integration of bioinspired, bio-derived, or biocompatible materials. These smart MNs possess unique characteristics, including skin adhesion, tunable dissolution kinetics, and environmental responsiveness, thereby enabling their deployment in wearable biosensors, rapid drug delivery systems, and responsive therapeutic platforms. This review specifically summarizes the progress of various stimulus-responsive MNs (e.g., pH-, temperature-, or electro-activated systems), which dynamically regulate drug release or modulate the therapeutic microenvironment in response to endogenous or exogenous signals such as pH variations, temperature fluctuations, and reactive oxygen species (ROS). Collectively, these smart MN systems open up new avenues for the clinical treatment and management of diabetes, cancer, and chronic cutaneous disorders.

Approximately 72% of non-small cell lung cancer (NSCLC) cases harbor p53 mutations or deletions, making mRNA-based p53 restoration a promising therapeutic strategy. However, achieving efficient and safe mRNA delivery remains a major challenge. Here, we developed multilayer-like peptide-lipid nanoparticles (PLNPs) for p53 mRNA delivery to NSCLC. The rationally designed peptide lipid CDO, which features a tri-ornithine headgroup and acid-labile carbamate linkages, exhibits strong binding affinity with mRNA. This interaction promotes the formation of PLNPs with a compact, dense architecture, characterized by a low radius of gyration (Rg) and minimal solvent-accessible surface area (SASA), enabling highly efficient mRNA encapsulation (>92%) and enhanced nanoparticle stability. The strong mRNA binding, combined with the tailored lipid structure, further facilitates improved cellular uptake and efficient endosomal escape, while maintaining excellent biocompatibility. PLNPs mediated highly efficient transfection (>96%), restored functional p53 protein, and subsequently induced cell cycle arrest and apoptosis in p53-null NCI-H1299 cells. In vivo, systemically administered p53 mRNA-PLNPs preferentially accumulated in tumor tissues, reactivated p53 signaling, activated the mitochondrial apoptotic pathway, and suppressed tumor growth by approximately 90% in mouse xenograft models, with minimal systemic toxicity. These results demonstrate PLNPs as a safe and effective mRNA delivery platform for p53 restoration therapy, offering a translatable treatment strategy for p53-deficient NSCLC.

Gene therapy represents a promising strategy for treating a range of diseases. Non-viral gene delivery systems, including lipid nanoparticles (LNPs), polymer micelles, and liposomes, enable the tissue-specific delivery of genetic sequences and promote the expression of functional proteins in target cells. Compared with traditional carriers, LNPs possess distinct, mechanistically supported advantages: high biosafety with less than 5% cytotoxicity in most primary cells and minimal systemic inflammation in preclinical models, good reproducibility with a coefficient of variation less than 10% for particle size and zeta potential, and efficient delivery of nucleic acids such as DNA, mRNA, and siRNA with transfection efficiencies comparable to those of viral vectors. This review summarizes recent advances in LNP-based delivery platforms, with a focus on their structure-activity relationships and the underlying mechanisms of nucleic acid delivery. It further discusses key challenges in clinical translation, including limited targeting specificity, concerns regarding long-term biocompatibility, difficulties in manufacturing scale-up, and regulatory hurdles. Additionally, the article highlights applications in oncology, for instance the delivery of tumor-suppressor genes, mRNA vaccines, and siRNA-mediated oncogene silencing, as well as applications in other therapeutic areas. Notably, we examine pioneering strategies designed to overcome these limitations, such as selective organ targeting (SORT) nanoparticles and biodegradable ionizable lipids including C12-200, which enhance tissue-specific delivery while reducing inflammatory responses. By integrating insights from lipid chemistry, formulation science, and translational data, this review provides a forward-looking perspective on the role of LNPs in cancer immunotherapy and regenerative medicine, while helping establish a framework for the design and optimization of next-generation nucleic acid delivery systems.

Solid tumors pose a spatial “delivery-at-depth” bottleneck: therapeutics that reach tumors often remain sequestered near vessels and fail to distribute uniformly into tumor cores. This limitation arises from heterogeneous perfusion, elevated interstitial fluid pressure, and dense extracellular matrix, which together restrict convection–diffusion balance and amplify binding-site barriers. We organize transformable and bioinspired nanomedicines using a barrier-centric lens and summarize five strategy families to deepen and homogenize intratumoral transport: (i) stimuli-responsive size/charge switching, (ii) microenvironment remodeling to restore perfusion and decompress stroma, (iii) ligand-guided transcytosis and CendR pathway engagement, (iv) cell-based and biomimetic vectors leveraging homing and immune evasion, and (v) multistage designs that sequence priming, switching, and payload activation. We compare representative systems by trigger specificity, activation timing, affinity tuning, and corona susceptibility, and highlight recurring failure modes including stimulus heterogeneity, premature/off-target activation, and escalating chemistry–manufacturing–controls burdens with added components. We conclude with translational priorities: couple barrier priming with a single well-characterized switching event, favor moderated or activatable affinity to avoid perivascular trapping, and validate spatial gains using standardized intratumoral distribution metrics linked to therapeutic endpoints.

Precisely targeted delivery of antitumor agents is a key strategy for enhancing cancer treatment efficacy. By leveraging specific tumor characteristics, functional modifications can construct highly selective delivery systems to optimize nanomedicine distribution at tumor sites. Owing to their editable sequences, peptides can be engineered into various targeting ligands for nanomaterial functionalization. Through specific receptor-ligand interactions, these modified nanomaterials achieve enhanced tumor-specific localization and deep penetration, enabling precise therapeutic agent delivery and improved treatment outcomes. This paper systematically reviews recent advances in peptide-based nanomaterials for tumor-targeted therapy. Based on molecular recognition, we present their applications in targeting the tumor microenvironment (TME) (including vasculature,immune cells, extracellular matrix, and associated fibroblasts), tumor cells, and organelles (such as mitochondria, endoplasmic reticulum [ER], Golgi apparatus, and nucleus). Furthermore, we provide an in-depth discussion of the opportunities and challenges these materials face in drug-targeted delivery, aiming to support the advancement of tumor-targeting nanomedicine.

Combination therapies hold significant promise for breast cancer treatment; however, conventional delivery systems often lack precise control over intracellular drug release, limiting delivery efficiency and therapeutic synergy. To address this, we engineered triple stimuli-responsive nanoparticles (HAP/PDA NPs) by coating prodrug HA-PPT (HAP; HA = hyaluronic acid, PPT = podophyllotoxin) with ester and disulfide bonds onto polydopamine (PDA) cores for synergistically combining chemotherapy, photothermal therapy, and immunotherapy. HAP/PDA NPs exhibited tumor microenvironment-responsive drug release triggered by low pH, high glutathione levels, and localized heat, achieving a cumulative PPT release of 90.9% under triple-stimuli conditions. Furthermore, the NPs enhanced photpthermal therapy efficacy by downregulating heat shock protein 70 expression, mitigating thermoresistance. Notably, the mechanism involved suppression of the immune checkpoint fibrinogen-like protein 1 (FGL-1) by HAP/PDA NPs via the JAK2/STAT3 axis, with FGL-1 expression reduced to approximately 40% of the control level, thereby reversing immunosuppression to activate antitumor immunity and drive primary tumor regression. As a result, this multimodal approach enabled complete inhibition of tumor growth in some subjects and maintained high efficacy with a markedly lower PPT dose (one-third of the conventional dose). These findings offer a mechanistic paradigm for designing precision nanomedicines that co-target molecular and immune pathways for improved combination therapy in refractory breast cancer.

The blood–brain barrier (BBB) protects the brain; however, it also severely limits drug delivery during glioma therapy. Notably, promising nanotechnology solutions provide biocompatible platforms with improved targeting, enhanced stability, and controlled release. This review outlines the physiological features of the BBB and summarizes the recent advances in nanotechnology-enabled strategies for glioma theranostics. In this review, the following three major approaches are highlighted: (i) crossing the BBB via transcellular transport, including carrier-mediated, receptor-mediated, and adsorption-mediated transcytosis; (ii) enhancing the BBB permeability with physical or chemical modulation, including focused ultrasound, hypertonic agents, electroporation, and magnetic stimulation; and (iii) bypassing the BBB by administering drugs via intrathecal, convection-enhanced, and intranasal routes as well as laser interstitial thermotherapy. Despite substantial advancements, challenges persist, including an incomplete understanding of penetration mechanisms, safety concerns, and the lack of reliable translational models. Thus, integrating nanotechnology with innovative delivery strategies provides promising strategies for more effective and precise glioma theranostics.

Clinical application of podophyllotoxin (PPT) is significantly hampered by poor aqueous solubility and considerable systemic toxicity. Herein, we engineered dual-targeting and dual-cleavable prodrug micelles (HPMs) by conjugating PPT to hyaluronic acid (HA) backbone via a flexible, dual-responsive spacer, adipic dihydrazide-3,3'-dithiodipropionic acid (ADH-DTDPA). In vitro, HPMs demonstrated efficient CD44-mediated internalization in NCI-H1299 cells and rapidly disassembled under tumor microenvironment (TME) conditions (pH 5.0/GSH). Crucially, microscale thermophoresis (MST) provided quantitative evidence of the targeting mechanism, revealing a high binding affinity (KD = 15.3 μM) for the CD44 receptor. In vivo, this design achieved effective accumulation of the micelles at tumor sites. Notably, HPMs (10 mg/kg) achieved superior tumor inhibition compared to free PPT (15 mg/kg) without inducing hepatotoxicity or nephrotoxicity. These findings provide a safe delivery strategy to overcome the clinical limitations of PPT and offer quantitative molecular insights into the rational design of targeted nanomedicines for lung cancer therapy.

Cancer is a worldwide public health problem that poses a serious threat to human health. Drug therapy, as the mainstay of cancer treatment, relies on carriers for the in vivo delivery of chemotherapeutic or nucleic acid-based drugs. Traditional drug delivery carriers have shortcomings, however, including a lack of targeting, uncontrollable release of drugs, and low stability, potentially leading to toxic side effects and reducing their antitumor efficacy. Advances in nanotechnology and biomedicine have furthered the development of stimuli-responsive nanodelivery systems, which can be used to realize the accumulation and on-demand release of drugs and reduce the required drug dosage and toxicity. Hyaluronic acid (HA), as a natural anionic polysaccharide with excellent biocompatibility, an easily modified structure, and the ability to target cancer cells, is a US Food and Drug Administration-approved biomaterial that is ideal for the construction of stimuli-responsive nanodelivery systems. Herein, we review HA-based stimuli-responsive nanodelivery systems including various HA-modified structures. We summarize the feasibility and effectiveness of these systems in cancer therapy according to their roles as endogenous- (pH, redox, enzyme, and hypoxia) or exogenous- (light, temperature, ultrasound, and magnetism) stimuli-responsive systems. We also discuss the problems and challenges in the development of HA-based stimuli-responsive nanodelivery systems and the perspectives for future development. This review highlights the great potential of HA-based stimuli-responsive nanodelivery systems for use in precision cancer treatment and controlled drug release.

Subcellular targeted therapy has recently emerged as a significant approach in cancer treatment. Mitochondria, as crucial organelles that not only provide cellular energy but also play roles in cell differentiation, signal transmission, reactive oxygen species production, apoptosis, and calcium homeostasis, are considered potential targets for cancer therapy. Silver sulfide quantum dots (Ag2S QDs) have demonstrated exceptional capabilities in near-infrared fluorescence and photoacoustic imaging as well as photothermal treatment. Therefore, the development of Ag2S QDs with mitochondrial-targeting ability is of particular significance. Herein, we developed a simple method for synthesizing aqueous-phase Ag2S QDs using lipoic acid, an enzymatic substrate involved in cellular respiration, as a ligand and mitochondrial-targeting molecule. These Ag2S QDs, which exhibit excellent water solubility and biocompatibility, can be produced in a single step and act as a mitochondrial-targeted theranostics. By adsorbing doxorubicin (DOX), we successfully created multifunctional nanoprobes called Ag2S-DOX. In vitro and in vivo experiments demonstrated that Ag2S-DOX was suitable for fluorescence and photoacoustic dual-mode imaging as well as synergistic mitochondrial-targeted chemotherapy and photothermal treatment, offering a promising strategy for tumor therapy.

The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system is a versatile genome editing technology that holds tremendous promise for the treatment of various diseases. Although several delivery technologies such as electroporation, viral vectors, and lipid nanoparticles have already shown promise in preclinical and clinical applications for hematological and neuromuscular genetic disorders, in vivo application is still restricted by the inefficient delivery of CRISPR/Cas9 components. Herein, by employing the tripeptide lipid N,N-ditetradecyloxyamidoethyl trimeric ornithine amide (CDO) and polyethylenimine (PEI), we constructed novel ternary systems (pDNA/PEI/CL) for the delivery of pDNA encoding Cas9 and single-guide RNAs (sgRNAs) targeting the VEGFR2 gene. The pDNA/PEI/CL delivery systems were fabricated by condensing pDNA with PEI, followed by coating with cationic liposomes composed of CDO. This system demonstrated high transfection efficiency, successfully delivering CRISPR/Cas9 to A549 and MCF-7 cells with efficiencies of up to 91.0% (n = 3, P < 0.001), while also exhibiting lower cytotoxicity. Notably, the sgRNA1/P1/C1 complex achieved higher genome editing efficiencies than sgRNA3/P1/C1, with 38.6% vs 31.0% in A549 cells (n = 3, P < 0.01) and 26.45% vs 20.18% in MCF-7 cells (n = 3, P < 0.01). Western blot analysis showed that VEGFR2 expression decreased by 48.1% in A549 and 44.3% in MCF-7 cells, while PI3K levels were reduced by 39.6% and 42.8%, respectively. This suppression of the PI3K/Akt signaling pathway led to cell cycle arrest, thereby inhibiting tumor cell proliferation and migration while promoting apoptosis. Furthermore, animal experiments validated the antitumor efficacy, highlighting the translational potential of this platform in cancer therapy. Collectively, these findings highlight the potential of the ternary complex system as a robust and biocompatible CRISPR/Cas9 delivery strategy, offering a promising avenue for gene therapy in cancer and other genetic diseases.

Quercetin is a natural flavonoid found in many plants which has various pharmacological activities including antitumor effect. However, the poor water solubility and bioavailability limit the potential benefits of quercetin for patients. Thus, modifying quercetin structure and developing actively targeted drug delivery systems are extremely important for tumor precision therapy. Herein, polymer-drug conjugates dextran-quercetin (D-Q) and cRGD-dextran (R-D) were synthesized by grafting quercetin and polypeptide cRGDfk (Arg-Gly-Asp-(D-Phe)-Lys) to dextran. Then cRGD-modified dextran-quercetin polymer micelles (R-D-Q) were constructed by self-assembling of D-Q and R-D. R-D-Q micelles possessed appropriate particle size (133.4 nm), nearly neutral potential (8.14 mV) and excellent drug-loading efficiency (13.1 %) and achieved higher cytotoxicity, apoptosis induction and penetration to human breast cancer MCF-7 cells than the micelles unmodified with cRGD, which were ascribed to cRGD-integrin mediated transcytosis. R-D-Q micelles effectively suppressed tumor growth in tumor-bearing mice by delivering more quercetin throughout the tumor tissue. And R-D-Q micelles could promote the apoptosis of tumor cells by activating p38 and JNK signal pathways and suppressing ERK signal pathway. In addition, R-D-Q micelles had no damage to normal tissues of mice at therapeutic dose. These results indicate promising prospects for R-D-Q micelles as an effective drug delivery system against tumor.

Multi-drug resistant microbes (MDRMs) present a significant threat to human health. Silver nanoparticles possess broad-spectrum antimicrobial properties, but the potential Ag+ ion release and toxicity on primary cells drawback the clinical application. In this study, imidazolylhydrazine was employed to cross-link chitosan into nanogels and subsequently to synthesize nanoconfined silver nanocrystallines. These silver nanocrystallines are predominantly characterized by (111) crystalline facets, featuring a high Ag0 atomic density and an approximate size of 3 nm. these nanocrystallines demonstrated exceptional visible light bactericidal properties, particularly against MDRMs, attributable to a threefold enhancement in reactive oxygen species (ROS) generation efficiency compared to silver nanoparticles. Remarkably, thanks to the nanoconfined domains of the silver nanocrystallines embedded within the nanogel, along with the gel's strong coordination capabilities with Ag through its imidazole, hydrazide, and amino groups, as well as the proton buffering capacity of imidazole, the release of silver ions in the body fluid environment was not significantly observed at any stage of the wound recovery. This ensures exceptional biocompatibility for postoperative wound spraying. The nanoconfined Ag nanocrystalline platform emerges as a novel prospect for wound sterilization.

Background Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. Methods Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. Results SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. Conclusions This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.

Liposomes have been extensively applied in gene and drug delivery. It is indicated in many studies that cationic lipids possess a certain degree of cytotoxicity, primarily induced by the lipid head group. In this study, we investigated the cytotoxic mechanisms of peptide headgroup lipid (CDO14) and quaternary ammonium salt headgroup lipid (CDA14) on the NCI-H460 and MRC-5 cell lines. Both lipids were synthesized in our laboratory and with high transfection efficiency. The differences in changes of relevant proteins during the process of inducing cell apoptosis were compared at the cellular level between the two lipids. The results showed that both types of liposomes could lead to an increase in intracellular reactive oxygen species, a decrease in ATP content, a decrease in mitochondrial membrane potential, an increase in cytochrome c content, an increase in the BAX/BCL-2 ratio, and an increase in cleaved caspase-3 content. Among these changes, the variations in CDA14 were more significant than those in CDO14. Additionally, the cellular uptake of CDA14 was significantly higher than that of CDO14. These results suggested that the cytotoxicity of quaternary ammonium salt-based lipids was higher than that of peptide-based lipids. The cytotoxicity of cationic lipids is related to their head group structure, and their cytotoxic effect is mainly achieved by activating caspase-dependent endogenous apoptosis.

Sucrose esters (SEs) have great potential in the field of nucleic acid delivery due to their unique physical and chemical properties and good biosafety. However, the mechanism of the effect of SEs structure on delivery efficiency has not been studied. The liposomes containing peptide lipids and SEs were constructed, and the effects of SEs on the interaction between the liposomes and DNA were studied. The addition of SEs affects the binding rate of liposomes to DNA, and the binding rate gradually decreases with the increase of SEs’ carbon chain length. SEs also affect the binding site and affinity of liposomes to DNA, promoting the aggregation of lipids to form liposomes, where DNA wraps around or compresses inside the liposomes, allowing it to compress DNA without damaging the DNA structure. COL-6, which is composed of sucrose laurate, exhibits the optimal affinity for DNA, and SE promotes the formation of ordered membrane structure and enhances membrane stability, so that COL-6 exhibits a balance between rigidity and flexibility, and thus exhibits the highest delivery efficiency of DNA among these formulations. This work provides theoretical foundations for the application of SE in gene delivery and guides for the rational design of delivery systems.