Tumor vaccines have become a crucial strategy in cancer immunotherapy. Challenges of traditional tumor vaccines include inadequate immune activation and low efficacy of antigen delivery. Nanoparticles, with their tunable properties and versatile functionalities, have redefined the landscape of tumor vaccine design. In this review, we outline the multifaceted roles of nanoparticles in tumor vaccines, ranging from their capacity as delivery vehicles to their function as immunomodulatory adjuvants capable of stimulating anti-tumor immunity. We discuss how this innovative approach significantly boosts antigen presentation by leveraging tailored nanoparticles that facilitate efficient uptake by antigen-presenting cells. These nanoparticles have been meticulously designed to overcome biological barriers, ensuring optimal delivery to lymph nodes and effective interaction with the immune system. Overall, this review highlights the transformative power of nanotechnology in redefining the principles of tumor vaccines. The intent is to inform more efficacious and precise cancer immunotherapies. The integration of these advanced nanotechnological strategies should unlock new frontiers in tumor vaccine development, enhancing their potential to elicit robust and durable anti-tumor immunity.

Although immunotherapy is currently one of the most promising methods for cancer treatment, its clinical application is limited due to issues such as excessive autoimmune responses and lack of specificity. Therefore, there is a need to improve immunotherapy by integrating emerging medical technologies with traditional treatments. The activation of the cGAS-STING pathway plays a crucial role in innate immunity and antiviral defense, making it highly promising for immunotherapy and attracting significant attention. In recent years, research on nanomaterials and immunotherapy has achieved groundbreaking progress in the medical field. Due to their unique size, shape, stiffness, surface effects, and quantum size effects, nanomaterials can either carry STING activators or directly activate the STING pathway, offering new opportunities for tumor-specific immunotherapy. These unique advantages of nanomaterials have opened up broader prospects for nanoparticle-based therapies targeting the STING pathway. This paper summarizes the current research on utilizing nanomaterials to activate the STING pathway, detailing the characteristics, classifications, and different approaches for targeting tumor cells. Additionally, it focuses on the latest advancements in combined nanotherapies based on cGAS-STING pathway activation, including the integration of nanomaterial-mediated STING pathway activation with immunotherapy, radiotherapy, chemotherapy, targeted therapy, and photodynamic therapy. This provides new ideas for nanoparticle-based combination therapies involving the STING pathway.

The high recurrence rate of hepatocellular carcinoma (HCC) and poor prognosis after medical treatment reflects the necessity to improve the current chemotherapy protocols, particularly drug delivery methods. Development of targeted and efficient drug delivery systems (DDSs), in all active, passive and stimuli-responsive forms for selective delivery of therapeutic drugs to the tumour site has been extended to improve efficacy and reduce the severe side effects. Recent advances in nanotechnology offer promising breakthroughs in the diagnosis, treatment and monitoring of cancer cells. In this review, the specific design of DDSs based on the different nano-particles and their surface engineering is discussed. In addition, the innovative clinical studies in which nano-based DDS was used in the treatment of HCC were highlighted.

Due to the intrinsic non-invasive nature, cost-effectiveness, high safety, and real-time capabilities, besides diagnostic imaging, ultrasound as a typical mechanical wave has been extensively developed as a physical tool for versatile biomedical applications. Especially, the prosperity of nanotechnology and nanomedicine invigorates the landscape of ultrasound-based medicine. The unprecedented surge in research enthusiasm and dedicated efforts have led to a mass of multifunctional micro-/nanosystems being applied in ultrasound biomedicine, facilitating precise diagnosis, effective treatment, and personalized theranostics. The effective deployment of versatile ultrasound-based micro-/nanosystems in biomedical applications is rooted in a profound understanding of the relationship among composition, structure, property, bioactivity, application, and performance. In this comprehensive review, we elaborate on the general principles regarding the design, synthesis, functionalization, and optimization of ultrasound-based micro-/nanosystems for abundant biomedical applications. In particular, recent advancements in ultrasound-based micro-/nanosystems for diagnostic imaging are meticulously summarized. Furthermore, we systematically elucidate state-of-the-art studies concerning recent progress in ultrasound-based micro-/nanosystems for therapeutic applications targeting various pathological abnormalities including cancer, bacterial infection, brain diseases, cardiovascular diseases, and metabolic diseases. Finally, we conclude and provide an outlook on this research field with an in-depth discussion of the challenges faced and future developments for further extensive clinical translation and application.

Hepatocellular carcinoma (HCC) represents one of the deadliest cancers globally, making the search for more effective diagnostic and therapeutic approaches particularly crucial. Aptamer-functionalized nanomaterials (AFNs), an innovative nanotechnology, have paved new pathways for the targeted diagnosis and treatment of HCC. Initially, we outline the epidemiological background of HCC and the current therapeutic challenges. Subsequently, we explore in detail how AFNs enhance diagnostic and therapeutic efficiency and reduce side effects through the specific targeting of HCC cells and the optimization of drug delivery. Furthermore, we address the challenges faced by AFNs in clinical applications and future research directions, with a particular focus on enhancing their biocompatibility and assessing long-term effects. In summary, AFNs represent an avant-garde therapeutic approach, opening new avenues and possibilities for the diagnosis and treatment of HCC.

Hypoxia-associated radioresistance in rectal cancer (RC) has severely hampered the response to radioimmunotherapy (iRT), necessitating innovative strategies to enhance RC radiosensitivity and improve iRT efficacy. Here, a catalytic radiosensitizer, DMPtNPS, and a STING agonist, cGAMP, are integrated to overcome RC radioresistance and enhance iRT. DMPtNPS promotes efficient X-ray energy transfer to generate reactive oxygen species, while alleviating hypoxia within tumors, thereby increasing radiosensitivity. Mechanistically, the transcriptomic and immunoassay analysis reveal that the combination of DMPtNPS and RT provokes bidirectional regulatory effects on the immune response, which may potentially reduce the antitumor efficacy. To mitigate this, cGAMP is loaded into DMPtNPS to reverse the negative impact of DMPtNPS and RT on the tumor immune microenvironment (TiME) through the type I interferon-dependent pathway, which promotes cancer immunotherapy. In a bilateral tumor model, the combination treatment of RT, DMPtNPS@cGAMP, and αPD-1 demonstrates a durable complete response at the primary site and enhanced abscopal effect at the distant site. This study highlights the critical role of incorporating catalytic radiosensitizers and STING agonists into the iRT approach for RC.

Mesoporous silica nanoparticles (MSNs) are recognized as a prime example of nanotechnology applied in the biomedical field, due to their easily tunable structure and composition, diverse surface functionalization properties, and excellent biocompatibility. Over the past two decades, researchers have developed a wide variety of MSNs-based nanoplatforms through careful design and controlled preparation techniques, demonstrating their adaptability to various biomedical application scenarios. With the continuous breakthroughs of MSNs in the fields of biosensing, disease diagnosis and treatment, tissue engineering, etc., MSNs are gradually moving from basic research to clinical trials. In this review, we provide a detailed summary of MSNs in the biomedical field, beginning with a comprehensive overview of their development history. We then discuss the types of MSNs-based nanostructured architectures, as well as the classification of MSNs-based nanocomposites according to the elements existed in various inorganic functional components. Subsequently, we summarize the primary purposes of surface-functionalized modifications of MSNs. In the following, we discuss the biomedical applications of MSNs, and highlight the MSNs-based targeted therapeutic modalities currently developed. Given the importance of clinical translation, we also summarize the progress of MSNs in clinical trials. Finally, we take a perspective on the future direction and remaining challenges of MSNs in the biomedical field.

The development of smart theranostic nanoplatforms has gained great interest in effective cancer treatment against the complex tumor microenvironment (TME), including weak acidity, hypoxia, and glutathione (GSH) overexpression. Herein, a TME-responsive nanoplatform named PMICApt /ICG, based on PB:Mn&Ir@CaCO3 Aptamer /ICG, is designed for the competent synergistic photothermal therapy and photodynamic therapy (PDT) under the guidance of photothermal and magnetic resonance imaging. The nanoplatform's aptamer modification targeting the transferrin receptor and the epithelial cell adhesion molecule on breast cancer cells, and the acid degradable CaCO3 shell allow for effective tumor accumulation and TME-responsive payload release in situ. The nanoplatform also exhibits excellent PDT properties due to its ability to generate O2 and consume antioxidant GSH in tumors. Additionally, the synergistic therapy is achieved by a single wavelength of near-infrared laser. RNA sequencing is performed to identify differentially expressed genes, which show that the expressions of proliferation and migration-associated genes are inhibited, while the apoptosis and immune response gene expressions are upregulated after the synergistic treatments. This multifunctional nanoplatform that responds to the TME to realize the on-demand payload release and enhance PDT induced by TME modulation holds great promise for clinical applications in tumor therapy.

Over the past several decades, the importance of the tumor mechanical microenvironment (TMME) in cancer progression or cancer therapy has been recognized by researchers worldwide. The abnormal mechanical properties of tumor tissues include high mechanical stiffness, high solid stress, and high interstitial fluid pressure (IFP), which form physical barriers resulting in suboptimal treatment efficacy and resistance to different types of therapy by preventing drugs infiltrating the tumor parenchyma. Therefore, preventing or reversing the establishment of the abnormal TMME is critical for cancer therapy. Nanomedicines can enhance drug delivery by exploiting the enhanced permeability and retention (EPR) effect, so nanomedicines that target and modulate the TMME can further boost antitumor efficacy. Herein, we mainly discuss the nanomedicines that can regulate mechanical stiffness, solid stress, and IFP, with a focus on how nanomedicines change abnormal mechanical properties and facilitate drug delivery. We first introduce the formation, characterizing methods and biological effects of tumor mechanical properties. Conventional TMME modulation strategies will be briefly summarized. Then, we highlight representative nanomedicines capable of modulating the TMME for augmented cancer therapy. Finally, current challenges and future opportunities for regulating the TMME with nanomedicines will be provided.

Cancer is ranked as the second leading cause of death globally. Traditional cancer therapies including chemotherapy are flawed, with off-target and on-target toxicities on the normal cells, requiring newer strategies to improve cell selective targeting. The application of nanomaterial has been extensively studied and explored as chemical biology tools in cancer theranostics. It shows greater applications toward stability, biocompatibility, and increased cell permeability, resulting in precise targeting, and mitigating the shortcomings of traditional cancer therapies. The nanoplatform offers an exciting opportunity to gain targeting strategies and multifunctionality. The advent of nanotechnology, in particular the development of smart nanomaterials, has transformed cancer diagnosis and treatment. The large surface area of nanoparticles is enough to encapsulate many molecules and the ability to functionalize with various biosubstrates such as DNA, RNA, aptamers, and antibodies, which helps in theranostic action. Comparatively, biologically derived nanomaterials perceive advantages over the nanomaterials produced by conventional methods in terms of economy, ease of production, and reduced toxicity. The present review summarizes various techniques in cancer theranostics and emphasizes the applications of smart nanomaterials (such as organic nanoparticles (NPs), inorganic NPs, and carbon-based NPs). We also critically discussed the advantages and challenges impeding their translation in cancer treatment and diagnostic applications. This review concludes that the use of smart nanomaterials could significantly improve cancer theranostics and will facilitate new dimensions for tumor detection and therapy.

The catalytic and antioxidant properties of platinum nanoparticles (PtNPs) make them promising candidates for several applications in nanomedicine. However, an open issue, still shared among most nanomaterials, is the understanding on how internalized PtNPs, which are confined within endo-lysosomal compartments, can exert their activities. To address this problem, here we study the protective effect of 5 nm PtNPs on a human hepatic (HepG2) cell line exposed to dichlorodiphenylethylene (DDE) as a model of oxidative stress. Our results indicate that PtNPs are very efficient to reduce DDE-induced damage in HepG2 cells, in an extent that depends on DDE dose. PtNPs can contrast the unbalance of mitochondrial dynamics induced by DDE and increase the expression of the SOD2 mitochondrial enzyme that recovers cells from oxidative stress. Interestingly, in cells treated with PtNPs─alone or in combination with DDE─mitochondria form contact sites with a rough endoplasmic reticulum and endo-lysosomes containing nanoparticles. These findings indicate that the protective capability of PtNPs, through their intrinsic antioxidant properties and modulating mitochondrial functionality, is mediated by an inter-organelle crosstalk. This study sheds new light about the protective action mechanisms of PtNPs and discloses a novel nano-biointeraction mechanism at the intracellular level, modulated by inter-organelle communication and signaling.

While calcium-overload-mediated therapy (COMT) is a promising but largely untapped therapeutic strategy, combinatory therapy greatly boosts treatment outcomes with integrated merits of different therapies. Herein, a BPQD@CaO₂ -PEG-GPC3Ab nanoplatform is formulated by integrating calcium peroxide (CaO₂ ) and black phosphorus quantum dot (BPQD, photosensitizer) with active-targeting glypican-3 antibody (GPC3Ab), for combinatory photodynamic therapy (PDT) and COMT in response to acidic pH and near-infrared (NIR) light, wherein CaO₂ serves as the reservoir of calcium ions (Ca²⁺ ) and hydrogen peroxide (H₂ O₂ ). Navigated by GPC3Ab to tumor cells at acidic pH, the nanoparticle disassembles to CaO₂ and BPQD; CaO₂ produces COMT Ca²⁺ and H₂ O₂ , while H₂ O₂ makes oxygen (O₂ ) to promote PDT; under NIR irradiation BPQD facilitates not only the conversion of O₂ to singlet oxygen (¹ O₂ ) for PDT, but also moderate hyperthermia to accelerate NP dissociation to CaO₂ and BPQD, and conversions of CaO₂ to Ca²⁺ and H₂ O₂ , and H₂ O₂ to O₂ , to enhance both COMT and PDT. After supplementary ionomycin treatment to induce intracellular Ca²⁺ bursts, the multimodal therapeutics strikingly induce hepatocellular carcinoma apoptosis, likely through the activation of the calpains and caspases 12, 9, and 3, up-regulation of Bax and down-regulation of Bcl-2 proteins. This nanoplatform enables a mutually-amplifying and self-reinforcing synergistic therapy.

Cancer is a major cause of human death all over the world. Traditional cancer treatments include surgery, radiotherapy, chemotherapy, immunotherapy, and hormone therapy. Although these conventional treatment methods improve the overall survival rate, there are some problems, such as easy recurrence, poor treatment, and great side effects. Targeted therapy of tumors is a hot research topic at present. Nanomaterials are essential carriers of targeted drug delivery, and nucleic acid aptamers have become one of the most important targets for targeted tumor therapy because of their high stability, high affinity, and high selectivity. At present, aptamer-functionalized nanomaterials (AFNs), which combine the unique selective recognition characteristics of aptamers with the high-loading performance of nanomaterials, have been widely studied in the field of targeted tumor therapy. Based on the reported application of AFNs in the biomedical field, we introduce the characteristics of aptamer and nanomaterials, and the advantages of AFNs first. Then introduce the conventional treatment methods for glioma, oral cancer, lung cancer, breast cancer, liver cancer, colon cancer, pancreatic cancer, ovarian cancer, and prostate cancer, and the application of AFNs in targeted therapy of these tumors. Finally, we discuss the progress and challenges of AFNs in this field.

As an emerging two-dimensional nanomaterial with promising prospects, mono- or few-layer black phosphorus (BP) is potentially toxic to humans. We investigated the effects of two types of BPs on adult male mice through intratracheal instillation. Using the flow cytometry method, the generation, migration, and recruitment of immune cells in different organs have been characterized on days 1, 7, 14, and 21 post-exposure. Compared with small BP (S-BP, lateral size at ∼188 nm), large BP (L-BP, lateral size at ∼326 nm) induced a stronger stress lymphopoiesis and B cell infiltration into the alveolar sac. More importantly, L-BP dramatically increased peripheral neutrophil (NE) counts up to 1.9-fold on day 21 post-exposure. Decreased expression of the CXCR4 on NEs, an important regulator of NE retention in the bone marrow, explained the increased NE release into the circulation induced by L-BP. Therefore, BP triggers systemic inflammation via the disruption of both the generation and migration of inflammatory immune cells.

Photodynamic therapy (PDT) is a promising cancer treatment modality with advantages of minimal invasiveness, repeatable therapy, and mild systemic toxicity. However, the limited bioavailability of photosensitizer (PS), tumor hypoxia, and the presence of antiapoptotic proteins in cancer cells, has hampered the efficiency of PDT. To address these limitations, herein, we developed a hyaluronic acid (HA) based nanosystem (HA-Ce6-Hemin@DNA-Protamine NPs, HCH@DP) loaded with chlorin e6 (Ce6, as PS), hemin (as mimetic catalase) and antisense oligonucleotide (ASO) of B-cell lymphoma 2 (Bcl-2) anti-apoptosis protein via a simple electrostatic self-assembly method for enhanced PDT of hypoxic solid tumors. The HCH@DP can target deliver the PS and ASO to tumor cells via cancer cell overexpressed HA receptors (i.e., CD44 or RHAMM). The Ce6 was released from HA-ss-Ce6 (HSC conjugates) after the reaction of cleavable disulfide bond with glutathione (GSH), which recovered the fluorescence and phototoxicity of Ce6 upon laser irradiation. Meanwhile, the catalase-mimicking hemin (degradation of HA-eda-hemin by hyaluronidase) decomposed the tumor overdressed endogenous H2O2 to oxygen, which relieved tumor hypoxia and further overcome hypoxia-associated resistance of PDT. Furthermore, the inhibition of Bcl-2 expression by Bcl-2 ASO also greatly improved the cellular sensitivity to PDT. Both in vitro and in vivo results showed the tumor cell targeting ability, hypoxia relief and significantly enhanced antitumor PDT efficacy of HCH@DP for hypoxic tumor cells upon laser irradiation. Thus, by improving the target delivery of PS and ASO, relieving tumor hypoxia, and down-regulation of anti-apoptotic proteins, this HCH@DP nanosystem achieved enhanced PDT efficiency against hypoxic tumors. In general, our work provided a promising strategy to increase the utilization of key components (PS and oxygen) of PDT and the cell sensitivity to PDT by targeting co-delivery PS and oligonucleotides to tumor cells via a biocompatible HA based carrier, thereby achieving efficiently PDT treatment of hypoxic solid tumors with potential translation possibility. STATEMENT OF SIGNIFICANCE: The efficiency of PDT against solid tumor is severely restricted by the limited bioavailability of photosensitizer, tumor hypoxia, and the presence of antiapoptotic proteins in cancer cells. Herein, we have developed an activatable hyaluronic acid (HA) based nanosystem (HA-Ce6-Hemin@DNA-Protamine NPs, HCH@DP) via a simple electrostatic self-assembly method for PDT treatment of hypoxic solid tumors. The HCH@DP enabled to target co-delivery of photosensitizer and antisense oligonucleotide to tumor cells, overcoming tumor hypoxia through in situ oxygen production and improving cellular sensitivity by efficiently reducing anti-apoptosis effect of cancer cells for synergistically enhancing PDT efficiency. This work suggests a promising strategy to develop small molecule drug and oligonucleotides co-delivery nanoplatforms for efficiently PDT treatment of hypoxic solid tumor.

Primary liver cancer is the seventh-most-common cancer worldwide and the fourth-leading cause of cancer mortality. In the current era of precision medicine, the diagnosis and management of liver cancer are full of challenges and prospects. Mesoporous nanoparticles are often designed as specific carriers of drugs and imaging agents because of their special morphology and physical and chemical properties. In recent years, the design of the elemental composition and morphology of mesoporous nanoparticles have greatly improved their drug-loading efficiency, biocompatibility and biodegradability. Especially in the field of primary liver cancer, mesoporous nanoparticles have been modified as highly tumor-specific imaging contrast agents and targeting therapeutic medicine. Various generations of complexes and structures have been determined for the complicated clinical management requirements. In this review, we summarize these advanced mesoporous designs in the different diagnostic and therapeutic fields of liver cancer and discuss the relevant advantages and disadvantages of transforming applications. By comparing the material properties, drug-delivery characteristics and application methods of different kinds of mesoporous materials in liver cancer, we try to help determine the most suitable drug carriers and information media for future clinical trials. We hope to improve the fabrication of biomedical mesoporous nanoparticles and provide direct evidence for specific cancer management.

Malignant tumors, particularly those located in deep tissues, have always been a grievous threat to human health. Sonodynamic therapy (SDT) has recently attracted great attention due to deep tissue penetration. However, the lack of effective sonosensitizers and the poor therapeutic efficacy severely limit their wider use. Herein, dual-functionalized black phosphorus nanosheets (BP@PEI-PEG, i.e., PPBP) integrating black oxygen-deficient titanium dioxide particles (B-TiO₂) were successfully constructed (PPBP-B-TiO₂) for synergistic photothermal (PTT)/sonodynamic therapy. In these nanocomposites, black titanium dioxide can enhance the separation of electrons (e^-) and holes (h⁺) due to the oxygen-deficient structure and significantly improves the production of reactive oxygen species (ROS) for SDT, while the BP nanosheets endow the nanocomposites with a higher photothermal conversion capability for photothermal therapy (η = 44.1%) which can prolong the blood circulation and improve the O₂ supply. In vivo experiments prove that PPBP-B-TiO₂ nanocomposites exhibited outstanding tumor inhibition efficacy and excellent biocompatibility. This work provides a prospective platform for combined photothermal/sonodynamic cancer therapy.

Hepatocellular carcinoma (HCC) commonly emerges in an immunologically "cold" state, thereafter protects it away from cytolytic attack by tumor-infiltrating lymphocytes, resulting in poor response to immunotherapy. Herein, an acidic/photo-sensitive dendritic cell (DCs)-based neoantigen nano-vaccine has been explored to convert tumor immune "cold" state into "hot", and remodel tumor-associated neutrophils to potentiate anticancer immune response for enhancing immunotherapy efficiency. The nano-vaccine is constructed by SiPCCl2 -hybridized mesoporous silica with coordination of Fe(III)-captopril, and coating with exfoliated membrane of matured DCs by H22-specific neoantigen stimulation. The nano-vaccines actively target H22 tumors and induce immunological cell death to boost tumor-associated antigen release by the generation of excess 1 O2 through photodynamic therapy, which act as in situ tumor vaccination to strengthen antitumor T-cell response against primary H22 tumor growth. Interestingly, the nano-vaccines are also home to lymph nodes to directly induce the activation and proliferation of neoantigen-specific T cells to suppress the primary/distal tumor growth. Moreover, the acidic-triggered captopril release in tumor microenvironment can polarize the protumoral N2 phenotype neutrophils to antitumor N1 phenotype for improving the immune effects to achieve complete tumor regression (83%) in H22-bearing mice and prolong the survival time. This work provides an alternative approach for developing novel HCC immunotherapy strategies.

Photodynamic therapy (PDT) is a noninvasive therapy for cancer and bacterial infection. Metal-free semiconducting conjugated polymers (SCPS) with good stability and optical and electrical properties are promising photosensitizers (PSs) for PDT compared with traditional small-molecule PSs. This review analyzes the latest progress of strategies to improve PDT effect of linear, planar, and three-dimensional SCPS, including improving solubility, adjusting conjugated structure, enhancing PS-doped SCPs, and combining therapies. Moreover, the current issues, such as hypoxia, low penetration, targeting and biosafety of SCPS, and corresponding strategies, are discussed. Furthermore, the challenges and potential opportunities on further improvement of PDT for SCPs are presented.

A wide variety of nanomaterials have emerged in recent years with advantageous properties for a plethora of therapeutic and diagnostic applications. Such applications include drug delivery, imaging, anti-cancer therapy and radiotherapy. There is a critical need for further components which can facilitate therapeutic targeting, augment their physicochemical properties, or broaden their theranostic applications. Aptamers are single-stranded nucleic acids which have been selected or evolved to bind specifically to molecules, surfaces, or cells. Aptamers can also act as direct biologic therapeutics, or in imaging and diagnostics. There is a rich field of discovery at the interdisciplinary interface between nanomaterials and aptamer science that has significant potential across biomedicine. Herein, we review recent progress in aptamer-enabled materials and discuss pending challenges for their future biomedical application.

The identification of tumor cell-specific surface markers is a key step towards personalized cancer medicine, allowing early assessment and accurate diagnosis, and development of efficacious targeted therapies. Despite significant efforts, currently the spectrum of cell membrane targets associated with approved treatments is still limited, causing an inability to treat a large number of cancers. What mainly limits the number of ideal clinical biomarkers is the high complexity and heterogeneity of several human cancers and still-limited methods for molecular profiling of specific cancer types. Thanks to the simplicity, versatility and effectiveness of its application, cell-SELEX (Systematic Evolution of Ligands by Exponential Enrichment) technology is a valid complement to the present strategies for biomarkers' discovery. We and other researchers worldwide are attempting to apply cell-SELEX to the generation of oligonucleotide aptamers as tools for both identifying new cancer biomarkers and targeting them by innovative therapeutic strategies. In this review, we discuss the potential of cell-SELEX for increasing the currently limited repertoire of actionable cancer cell-surface biomarkers and focus on the use of the selected aptamers as components of innovative conjugates and nano-formulations for cancer therapy.

Intrinsic tumor microenvironment (TME)-related therapeutic resistance and nontumor-specific imaging have limited the application of imaging-guided cancer therapy. Herein, a TME-responsive MnO₂-based nanoplatform coupled with turn-on and always-on fluorescence probes was designed through a facile biomineralization method for imaging-guided photodynamic/chemodynamic/photothermal therapy (PDT/CDT/PTT). After the tumor-targeting delivery of the AuNCs@MnO₂-ICG@AS1411 (AMIT) nanoplatform via aptamer AS1411, the TME-responsive dissociation of MnO₂ generated sufficient O₂ and Mn²⁺ with the consumption of GSH for improving PDT efficacy and Fenton-like reaction-mediated CDT. Simultaneously, the released small-sized ICG and AuNCs facilitated PDT and PTT efficacy via the deep tumor penetration. Moreover, the turn-on fluorescence of AuNCs revealed the real-time TME-responsive MnO₂ degradation process, and the always-on ICG fluorescence enabled the in situ monitoring of the payload distribution in vitro and in vivo. The AMIT NPs also provided magnetic resonance and thermal imaging guidance for the enhanced PDT, CDT, and PTT. Therefore, this all-in-one nanosystem provides a simple and versatile strategy for multiple imaging-guided theranostic applications.

Hepatocellular carcinoma (HCC) is one of the most common malignant cancer in the world, which greatly threatens human health. However, the routine treatment strategies for HCC have failed to specifically eradicate the tumorigenic cells, leading to the occurrence of metastasis and recurrence. To improve treatment efficacies, the development of novel effective technologies is urgently required. Recently, nanotechnologies have gained the extensive attention in cancer targeted therapy, which could provide a promising way for HCC clinical practice. However, a successful cancer management depends on accurate diagnosis of the tumour along with precise therapeutic protocol, thereby predicting the tumour response to existing therapies. The synergistic effect of targeted therapeutic systems and imaging approaches (also called 'imaging-guided cancer treatment') may establish a more effective platform for individual cancer care. This review outlines the recent advanced nano-targeted and -traceable therapeutic strategies for HCC management. The multifunctional nano agents that have both diagnosis and therapy abilities are highlighted. Finally, we conclude with our perspectives on the future development and challenges of HCC nanotheranostics.

Photoactivated therapeutic strategies (photothermal therapy and photodynamic therapy), due to the adjusted therapeutic area, time and light dosage, have prevailed for the fight against tumors. Currently, the monotherapy with limited treatment effect and undesired side effects is gradually replaced by multimodal and multifunctional nanosystems. Mesoporous silica nanoparticles (MSNs) with unique physicochemical advantages, such as huge specific surface area, controllable pore size and morphology, functionalized modification, satisfying biocompatibility and biodegradability, are considered as promising candidates for multimodal photoactivated cancer therapy. Excitingly, the innovative nanoplatforms based on the mesoporous silica nanoparticles provide more and more effective treatment strategies and display excellent antitumor potential. Given the rapid development of antitumor strategies based on MSNs, this review summarizes the current progress in MSNs-based photoactivated cancer therapy, mainly consists of (1) photothermal therapy-related theranostics; (2) photodynamic therapy-related theranostics; (3) multimodal synergistic therapy, such as chemo-photothermal-photodynamic therapy, phototherapy-immunotherapy and phototherapy-radio therapy. Based on the limited penetration of irradiation light in photoactivated therapy, the challenges faced by deep-seated tumor therapy are fully discussed, and future clinical translation of MSNs-based photoactivated cancer therapy are highlighted.

To date, nanotechnology has increasingly been identified as a promising and efficient means to address a number of challenges associated with public health. In the past decade, two-dimensional (2D) biomaterials, as a unique nanoplatform with planar topology, have attracted explosive interest in various fields such as biomedicine due to their unique morphology, physicochemical properties and biological effect. Motivated by the progress of graphene in biomedicine, dozens of types of ultrathin 2D biomaterials have found versatile bio-applications, including biosensing, biomedical imaging, delivery of therapeutic agents, cancer theranostics, tissue engineering, as well as others. The effective utilization of 2D biomaterials stems from the in-depth knowledge of structure-property-bioactivity-biosafety-application-performance relationships. A comprehensive summary of 2D biomaterials for biomedicine is still lacking. In this comprehensive review, we aim to concentrate on the state-of-the-art 2D biomaterials with a particular focus on their versatile biomedical applications. In particular, we discuss the design, fabrication and functionalization of 2D biomaterials used for diverse biomedical applications based on the up-to-date progress. Furthermore, the interactions between 2D biomaterials and biological systems on the spatial-temporal scale are highlighted, which will deepen the understanding of the underlying action mechanism of 2D biomaterials aiding their design with improved functionalities. Finally, taking the bench-to-bedside as a focus, we conclude this review by proposing the current crucial issues/challenges and presenting the future development directions to advance the clinical translation of these emerging 2D biomaterials.

The low oxygen level in tumors significantly reduces the antitumor efficacy of photodynamic therapy (PDT). The provision of O₂ and monomeric hydrophobic photosensitizers (PSs) under physiological conditions would greatly help to shrink malignant tumors. We take advantage of the high porosity and multifunctionality of metal-organic frameworks (MOFs) to fabricate a simple all-in-one nanoplatform mediated by microneedle delivery to achieve synergistic O₂ evolution and chemophototherapy. An iron(III)-based MOF (MIL-100(Fe)) acted not only as a vehicle for the concurrent delivery of zinc phthalocyanine (ZnPc) and doxorubicin hydrochloride (Dox), but also to supply O₂ by decomposing hydrogen peroxide (H₂O₂) in the tumor microenvironment via a Fenton-like reaction. In vitro and in vivo experiments indicated that the nanoplatform had excellent biocompatibility and exerted enhanced anticancer effects. The encapsulated drug was sustainably released from the nanoplatform skeleton in response to acidic tumor microenvironments. Moreover, upon 660 nm light irradiation, ZnPc effectively produced reactive oxygen species (ROS) due to the reduction of hypoxia by MIL-100(Fe). A microneedle technique was adopted to directly deliver the nanoplatform into superficial tumors rather than via systemic circulation. Hence, this study provides a new strategy for more efficient chemophototherapy of hypoxic superficial tumors.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide, which lacks effective inhibition of progression and metastasis in the advanced clinical stage. Mesoporous silica nanoparticle (MSN)-based cytotoxic or immunoregulatory drug-loading strategies have attracted widespread attention in the recent years. As a representative of mesoporous biomaterials, MSNs have good biological characteristics and immune activation potential and can cooperate with adjuvants against HCC. This review summarizes the possible future development of the field from the perspective of tumor immunity and aims to stimulate the exploration of the immune mechanism of MSN-based therapy. Through this point of view, we hope to develop new clinical immune drugs that can be applied to HCC clinical management in the future.

Biomimetic membrane materials have been widely explored and developed for drug loading and tissue engineering applications due to their excellent biocompatibility and abundant reaction sites. However, novel cytomembrane mimics have been lacking for a long time. In this study, black phosphorus (BP) was used as the foundation for a new generation of promising cytomembrane mimics due to its multiple similarities to cytomembranes. Inspired by the dual function of endotoxins on membranes, we prepared a BP-based cytomembrane mimic with controllable antibacterial ability via electrostatic interaction between BP and [1-pentyl-1-quaternary ammonium-3-vinyl-imidazole]Br ([PQVI]Br). The release of PQVI could be manipulated in different conditions by adjusting the electrostatic force, thereby achieving controllable antibacterial ability. This report confirms the possibility of using BP as a new material to mimic cytomembranes and provides a new concept of controllable antibacterial action based on endotoxins.

Silica-based nanoframeworks have been extensively studied for diagnosing and treating hepatocellular carcinoma (HCC). Several reviews have summarized the advantages and disadvantages of these nanoframeworks and their use as drug-delivery carriers. Encouragingly, these nanoframeworks, especially those with metal elements or small molecular drugs doping into the skeleton structure or modifying onto the surface of nanoparticles, could be multifunctional components participating in HCC diagnosis and treatment rather than functioning only as drug-delivery carriers. Therefore, in this work, we described the research progress of silica-based nanoframeworks involved in HCC diagnosis (plasma biomarker detection, magnetic resonance imaging, positron emission tomography, photoacoustic imaging, fluorescent imaging, ultrasonography, etc.) and treatment (chemotherapy, ferroptotic therapy, radiotherapy, phototherapy, sonodynamic therapy, immunotherapy, etc.) to clarify their roles in HCC theranostics. Further, the future expectations and challenges associated with silica-based nanoframeworks were highlighted. We believe that this review will provide a comprehensive understanding for researchers to design novel, functional silica-based nanoframeworks that can effectively overcome HCC.

As a newly emerged mono-elemental nanomaterial, black phosphorus (BP) has been widely investigated for its fascinating physical properties, including layer-dependent tunable band gap (0.3-1.5 eV), high ON/OFF ratio (10⁴ ), high carrier mobility (10³ cm² V^-1 s^-1 ), excellent mechanical resistance, as well as special in-plane anisotropic optical, thermal, and vibrational characteristics. However, the instability caused by chemical degradation of its surface has posed a severe challenge for its further applications. A focused BP/polymer strategy has more recently been developed and implemented to hurdle this issue, so at present BP/polymers have been developed that exhibit enhanced stability, as well as outstanding optical, thermal, mechanical, and electrical properties. This has promoted researchers to further explore the potential applications of black phosphorous. In this review, the preparation processes and the key properties of BP/polymers are reviewed, followed by a detailed account of their diversified applications, including areas like optoelectronics, bio-medicine, and energy storage. Finally, in accordance with the current progress, the prospective challenges and future directions are highlighted and discussed.

Black phosphorus quantum dots(BPQDs) have shown a good application prospect in the field of tumor therapy due to their photoelectric effect and good biodegradability. Due to the active endocytosis and fast metabolic efficiency of tumor cells, BPQDs are easy to be absorbed by tumor cells. However, this does not guarantee that BPQDs will be completely targeted to tumor cells, and normal cells will also absorb BPQDs. Because the cell membrane is negatively charged, BPQDs are also negatively charged and are not easily absorbed by cells under the action of electrostatic repulsion. Surface pegylation is the most common modification method of black phosphorus at present. However, surface pegylation can reduce the uptake of BPQDs by tumor cells. Positive PEG is also easy to be recognized and swallowed by the reticuloendothelial system. The inherent instability and poor tumor targeting of BPQDs under physiological conditions limit further research and clinical application. For this purpose, we selected cationic polymer polyethylenimine (PEI) to modify BPQDs and then added RGD peptides targeting tumor cells. An outer layer of negatively charged PEG+DMMA makes the nanosystem more stable . In the acidic environment of the tumor, the PEG layer has a charge reversal, and the positively charged PEI and the RGD polypeptide BPQDs targeted by the tumor cells are released into the tumor cells. It provides a new method for efficiently and accurately transporting BPQDs, a novel photosensitive nanomaterial, into tumor cells for photodynamic therapy.

Achieving controlled and accurate delivery of photosensitizers (PSs) into tumor sites is a major challenge in conventional photodynamic therapy (PDT). Aptamer is a short oligonucleotide sequence (DNA or RNA) with a folded three-dimensional structure, which can selectively bind to specific small molecules, proteins, or the whole cells. Aptamers could act as ligands and be modified onto PSs or nanocarriers, enabling specific recognition and binding to tumor cells or their membrane proteins. The resultant aptamer-modified PSs or PSs-containing nanocarriers generate amounts of reactive oxygen species with light irradiation and obtain superior photodynamic therapeutic efficiency in tumors. Herein, we overview the recent progress in the designs and applications of aptamer-targeted photodynamic platforms for tumor therapy. First, we focus on the progress on the rational selection of aptamers and summarize the applications of aptamers which have been applied for targeted tumor diagnosis and therapy. Then, aptamer-targeted photodynamic therapies including various aptamer-PSs, aptamer-nanocarriers containing PSs, and aptamer-nano-photosensitizers are highlighted. The aptamer-targeted synergistically therapeutic platforms including PDT, photothermal therapy, and chemotherapy, as well as the imaging-guided theranostics, are also discussed. Finally, we offer an insight into the development trends and future perspectives of aptamer-targeted photodynamic platforms for tumor therapy.

Nanomaterial-related photothermal therapy has been intensively investigated for treatment of hepatocellular carcinoma (HCC). However, owing to the low specificity to tumors and easy excretion from the systemic circulation, the low dose of photoactive nanomaterials in solid tumors severely hinders the photothermal therapy applications for HCC. Herein, an innovative strategy for transarterial infusion photothermal therapy (TAIPPT) of VX2 tumors implanted in rabbits is reported. NIR-absorbing Prussian blue nanoparticles were prepared by microemulsion methods, which demonstrate excellent photothermal therapy capacity and satisfactory biocompatibility. Prussian blue nanoparticles are transarterially infused into VX2 tumors and irradiated for photothermal therapy. TAIPPT achieves fast and efficient delivery of nanoparticles into tumors and complete ablation by one-time transarterial infusion treatment. Furthermore, TAIPPT could activate the immune cells in rabbits and inhibit distant tumors. Our findings describe a promising strategy for tumor eradication and may benefit future clinical HCC patients.

Phosphorene, also known as black phosphorus (BP), is a two-dimensional (2D) material that has gained significant attention in several areas of current research. Its unique properties such as outstanding surface activity, an adjustable bandgap width, favorable on/off current ratios, infrared-light responsiveness, good biocompatibility, and fast biodegradation differentiate this material from other two-dimensional materials. The application of BP in the biomedical field has been rapidly emerging over the past few years. This article aimed to provide a comprehensive review of the recent progress on the unique properties and extensive medical applications for BP in bone, nerve, skin, kidney, cancer, and biosensing related treatment. The details of applications of BP in these fields were summarized and discussed.

Wonderful black phosphorus (BP) and some BP analogs (BPAs) have been increasingly studied for their biomedical applications owing to their fascinating properties and biodegradability, but opportunities and challenges have always coexisted in their study. Poor stability upon exposure to the natural environment is the major obstacle hampering their in vivo applications. BP/polymer and BPAs/polymer nanocomposites can not only efficiently prevent their oxidation and aggregation but also exhibit "biological activity" due to synergistic effects. In this review, we briefly describe the synthesis methods and stability strategies of BP/polymer and BPAs/polymer. Then, advances pertaining to their exciting therapeutic applications in various fields are systematically introduced, such as cancer therapy (phototherapy, drug delivery, and synergistic immunotherapy), bone regeneration, and neurogenesis. Some challenges for future clinical trials and possible directions for further study are finally discussed.

Zero-dimensional (0D) black phosphorus quantum dots (BPQDs), the new derivatives of black phosphorus (BP) nanomaterials, have attracted considerable attention since they were first prepared in 2015. Compared to traditional two-dimensional (2D) BP nanosheets, BPQDs exhibit some unique properties and demonstrate great potential for a broad range of applications, especially in the field of biomedicine. Due to the rapid development and substantial research interest in this area, it is urgent to review the current advances, challenges and near-future possibilities of BPQD-related biomedical research, which will benefit the further development of this field. This review is mainly focused on the latest progress of BPQD related applications in the biomedical field, including photothermal therapy (PTT), photodynamic therapy (PDT), drug delivery, biological imaging, etc. The challenges and future prospects are also discussed.