Microneedle‐Assisted,DC‐Targeted Codelivery of pTRP‐2 and Adjuvant of Paclitaxel for Transcutaneous Immunotherapy

This work aims at developing an immunotherapeutic strategy to deliver a cancer DNA vaccine targeting dendritic cells (DCs), to trigger their maturation and antitumor function, and reduce immune escape using a polymeric nanocomplex of paclitaxel (PTX)‐encapsulated sulfobutylether‐β‐cyclodextrin (SBE)/mannosylated N,N,N‐trimethylchitosan (mTMC)/DNA. To enhance DC‐targeting and revoke immunosuppression is the major challenge for eliciting effective antitumor immunity. This codelivery system is characterized by using low‐dose PTX as an adjuvant that is included inside SBE, and the PTX/SBE further serves as an anionic crosslinker to self‐assemble with the cationic mTMC/DNA polyplexes. This system is used in combination with a microneedle for transcutaneous vaccination. Once penetrating into the epidermis, the mannosylated nanocomplexes would preferentially deliver the pTRP‐2 DNA vaccine inside the DCs. Phenotypic maturation is demonstrated by the increased expression of costimulatory molecules of CD80 and CD86, and the elevated secretion of IL‐12p70. The mixed leucocyte reactions reveal that the PTX/SBE‐mTMC/DNA nanocomplexes enhance the proliferation of CD4+ and CD8+ T cells, and inhibit the generation of immune‐suppressive FoxP3+ T cells. The system shows high antitumor efficacy in vivo. The PTX/SBE‐mTMC/DNA nanocomplexes for DC‐targeted codelivery of DNA vaccine and adjuvant PTX yield synergistic effects on the DC maturation and its presenting functions, thus increasing immune stimulation and reducing immune escape.     

A Dual‐Bioresponsive Drug‐Delivery Depot for Combination of Epigenetic Modulation and Immune Checkpoint Blockade

Patients with advanced melanoma that is of low tumor‐associated antigen (TAA) expression often respond poorly to PD‐1/PD‐L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti‐PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH‐sensitive calcium carbonate nanoparticles (CaCO₃ NPs), which are then encapsulated in the ROS‐responsive hydrogel together with Zeb (Zeb‐aPD1‐NPs‐Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10‐melanoma‐bearing mice.     

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial‐Membrane‐Coated Nanoparticles

Neoantigens induced by random mutations and specific to an individual's cancer are the most important tumor antigens recognized by T cells. Among immunologically “cold” tumors, limited recognition of tumor neoantigens results in the absence of a de novo antitumor immune response. These “cold” tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs). Radiation therapy (RT) can enhance immune recognition of “cold” tumors, resulting in a more diversified antitumor T‐cell response, yet RT alone rarely results in a systemic antitumor immune response. Therefore, a multifunctional bacterial membrane‐coated nanoparticle (BNP) composed of an immune activating PC7A/CpG polyplex core coated with bacterial membrane and imide groups to enhance antigen retrieval is developed. This BNP can capture cancer neoantigens following RT, enhance their uptake in dendritic cells (DCs), and facilitate their cross presentation to stimulate an antitumor T‐cell response. In mice bearing syngeneic melanoma or neuroblastoma, treatment with BNP+RT results in activation of DCs and effector T cells, marked tumor regression, and tumor‐specific antitumor immune memory. This BNP facilitates in situ immune recognition of a radiated tumor, enabling a novel personalized approach to cancer immunotherapy using off‐the‐shelf therapeutics.     

Tumor Microenvironment‐Activatable Prodrug Vesicles for Nanoenabled Cancer Chemoimmunotherapy Combining Immunogenic Cell Death Induction and CD47 Blockade

Chemoimmunotherapy is reported to activate a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), which has initiated a number of clinical trials. However, current chemoimmunotherapy is restricted to a small fraction of patients due to low drug delivery efficacy and immunosuppression within the tumor microenvironment. A tumor microenvironment‐activatable prodrug vesicle for cancer chemoimmunotherapy using ICD is herein reported. The prodrug vesicles are engineered by integrating an oxaliplatin (OXA) prodrug and PEGylated photosensitizer (PS) into a single nanoplatform, which show tumor‐specific accumulation, activation, and deep penetration in response to the tumoral acidic and enzymatic microenvironment. It is demonstrated that codelivery of OXA prodrug and PS can trigger ICD of the tumor cells by immunogenic cells killing. The combination of prodrug vesicle‐induced ICD with Î ± CD47‐mediated CD47 blockade further facilitates dendritic cell (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity of ICD. CD47 blockade and ICD induction efficiently inhibit the growth of both primary and abscopal tumors, suppress tumor metastasis, and prevent tumor recurrence. Collectively, these results imply that boosting antitumor immunity using ICD induction and suppressing tumor immune evasion via CD47 blockade might be promising for improved cancer chemoimmunotherapy.     

Nanovaccines Mediated Subcutis-to-Intestine Cascade for Improved Protection against Intestinal Infections

Parenteral vaccines typically can prime systemic humoral immune response, but with limited effects on cellular and mucosal immunity. Here, a subcutis-to-intestine cascade for navigating nanovaccines to address this limitation is proposed. This five-step cascade includes lymph nodes targeting, uptaken by dendritic cells (DCs), cross-presentation of antigens, increasing CCR9 expression on DCs, and driving CD103⁺ DCs to mesenteric lymph nodes, in short, the LUCID cascade. Specifically, mesoporous silica nanoparticles are encapsulated with antigen and adjuvant toll-like receptor 9 agonist cytosine-phosphate-guanine oligodeoxynucleotides, and further coated by a lipid bilayer containing all-trans retinoic acid. The fabricated nanovaccines efficiently process the LUCID cascade to dramatically augment cellular and mucosal immune responses. Importantly, after being vaccinated with Salmonella enterica serovar Typhimurium antigen-loaded nanovaccine, the mice generate protective immunity against challenge of S. Typhimurium. These findings reveal the efficacy of nanovaccines mediated subcutis-to-intestine cascade in simultaneously activating cellular and mucosal immune responses against mucosal infections.     

PD‐1 Blockade Cellular Vesicles for Cancer Immunotherapy

Cancer cells resist to the host immune antitumor response via multiple suppressive mechanisms, including the overexpression of PD‐L1 that exhausts antigen‐specific CD8⁺ T cells through PD‐1 receptors. Checkpoint blockade antibodies against PD‐1 or PD‐L1 have shown unprecedented clinical responses. However, limited host response rate underlines the need to develop alternative engineering approaches. Here, engineered cellular nanovesicles (NVs) presenting PD‐1 receptors on their membranes, which enhance antitumor responses by disrupting the PD‐1/PD‐L1 immune inhibitory axis, are reported. PD‐1 NVs exhibit a long circulation and can bind to the PD‐L1 on melanoma cancer cells. Furthermore, 1‐methyl‐tryptophan, an inhibitor of indoleamine 2,3‐dioxygenase can be loaded into the PD‐1 NVs to synergistically disrupt another immune tolerance pathway in the tumor microenvironment. Additionally, PD‐1 NVs remarkably increase the density of CD8⁺ tumor infiltrating lymphocytes in the tumor margin, which directly drive tumor regression.     

Efficient internalization of peptide-conjugated SPIONs in dendritic cells for tumor targeting

Antigen delivery using nanoparticles becomes useful and novel strategy to develop immunotherapeutic approaches against cancer. In the current study, we examined the feasibility of SPIONs-mediated delivery of antigenic peptides to local tumor for application to cancer immunotherapy. SPIONs carrying murine melanoma antigens, hgp100(25-33) were prepared and used to test its efficacy in mouse model. Efficient uptake of peptide-conjugated SPIONs by murine dendritic cells (DCs) was shown, using NP labeled with the fluorescent dye Furthermore, potential targeting effect of SPIONs carrying tumor antigenic peptide was verified in vitro and in vivo. Our results demonstrate the feasibility of SPIONs-mediated antigen delivery for cancer immunotherapy and highlight the clinical potential of SPIONs for future cancer treatment with high efficacy.     

Construction of pH-Sensitive Nanovaccines Encapsulating Tumor Cell Lysates and Immune Adjuvants for Breast Cancer Therapy

The current immunotherapy strategies for triple negative breast cancer (TNBC) are greatly limited due to the immunosuppressive tumor microenvironment (TME). Immunization with cancer vaccines composed of tumor cell lysates (TCL) can induce an effective antitumor immune response. However, this approach also has the disadvantages of inefficient antigen delivery to the tumor tissues and the limited immune response elicited by single-antigen vaccines. To overcome these limitations, a pH-sensitive nanocalcium carbonate (CaCO₃) carrier loaded with TCL and immune adjuvant CpG (CpG oligodeoxynucleotide 1826) is herein constructed for TNBC immunotherapy. This tailor-made nanovaccine, termed CaCO₃@TCL/CpG, not only neutralizes the acidic TME through the consumption of lactate by CaCO₃, which increases the proportion of the M1/M2 macrophages and promotes infiltration of effector immune cells but also activates the dendritic cells in the tumor tissues and recruits cytotoxic T cells to further kill the tumor cells. In vivo fluorescence imaging study shows that the pegylated nanovaccine could stay longer in the blood circulation and extravasate preferentially into tumor site. Besides, the nanovaccine exhibits high cytotoxicity in 4T1 cells and significantly inhibits tumor growth of tumor-bearing mice. Overall, this pH-sensitive nanovaccine is a promising nanoplatform for enhanced immunotherapy of TNBC.     

Leveraging β-Adrenergic Receptor Signaling Blockade for Improved Cancer Immunotherapy Through Biomimetic Nanovaccine

The establishment of effective antitumor immune responses of vaccines is mainly limited by insufficient priming tumor infiltration of T cells and immunosuppressive tumor microenvironment (TME). Targeting β-adrenergic receptor (β-AR) signaling exerts promising benefits on reversing the suppressive effects directly on T cells, but it appears to have considerably limited antitumor performance when combined with vaccine-based immunotherapies. Herein, a tumor membrane-coated nanoplatform for codelivery of adjuvant CpG and propranolol (Pro), a β-AR inhibitor is designed. The biomimetic nanovaccine displayed an improved accumulation in lymph nodes and sufficient drug release, thereby inducing dendritic cell maturation and antigen presentation. Meanwhile, the integration of vaccination and blockade of β-AR signaling not only promoted the priming of the naive CD8+ T cells and effector T cell egress from lymph nodes, but also alleviated the immunosuppressive TME by decreasing the frequency of immunosuppressive cells and increasing the tumor infiltration of B cells and NK cells. Consequently, the biomimetic nanovaccines outperformed greater prophylactic and therapeutic efficacy than nanovaccines without Pro encapsulation in B16-F10 melanoma mice. Taken together, the work explored a biomimetic nanovaccine for priming tumor infiltration of T cells and immunosuppressive TME regulation, offering tremendous potential for a combined β-AR signaling-targeting strategy in cancer immunotherapy.     

Construction of CpG Delivery Nanoplatforms by Functionalized MoS2 Nanosheets for Boosting Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

Despite the promising achievements of immune checkpoint blockade (ICB) therapy for tumor treatment, its therapeutic effect against solid tumors is limited due to the suppressed tumor immune microenvironment (TIME). Herein, a series of polyethyleneimine (Mw = 0.8k, PEI_0.8k)-covered MoS₂ nanosheets with different sizes and charge densities are synthesized, and the CpG, a toll-like receptor-9 agonist, is enveloped to construct nanoplatforms for the treatment of head and neck squamous cell carcinoma (HNSCC). It is proved that functionalized nanosheets with medium size display similar CpG loading capacity regardless of low or high PEI_0.8k coverage owing to the flexibility and crimpability of 2D backbone. CpG-loaded nanosheets with medium size and low charge density (CpG@M_M-P_L) could promote the maturation, antigen-presenting capacity, and proinflammatory cytokines generation of bone marrow-derived dendritic cells (DCs). Further analysis reveals that CpG@M_M-P_L effectively boosts the TIME of HNSCC in vivo including DC maturation and cytotoxic T lymphocyte infiltration. Most importantly, the combination of CpG@M_M-P_L and ICB agents anti-programmed death 1 hugely improves the tumor therapeutic effect, inspiring more attempts for cancer immunotherapy. In addition, this work uncovers a pivotal feature of the 2D sheet-like materials in nanomedicine development, which should be considered for the design of future nanosheet-based therapeutic nanoplatforms.     

Personalized Cancer Immunotherapy via Transporting Endogenous Tumor Antigens to Lymph Nodes Mediated by Nano Fe3O4

While immunotherapy has a tremendous clinical potential to combat cancer, immune responses generated by conventional cancer immunotherapy remain not enough to completely eliminate tumors, mainly due to the tumor's immunosuppressive microenvironment and heterogeneity of tumor immunogenicity. To improve antitumor immune responses and realize personalized immunotherapy, in this report, endogenous tumor antigens (ETAs) that dynamically present on tumor cells are transported to lymph nodes (LNs). Based on the hypothesis that nano Fe₃O₄ (≈10 nm) could serve as the nanocarrier for transporting ETAs from the tumor to LNs, we wondrously find that Fe₃O₄ has a tremendous potential to improve cancer immunotherapy, because of its excellent protein‐captured efficiency and LNs‐targeted ability. To ensure the optimal ETAs‐bound efficiency of Fe₃O₄, a core–shell formulation (denoted as Ce6/Fe₃O₄‐L) is developed and specific release of Fe₃O₄ in tumor is enabled. These findings provide a simple and general strategy for boosting cytotoxic T‐cell response and realizing personalized cancer immunotherapy simultaneously.     

Endolysosomal‐Escape Nanovaccines through Adjuvant‐Induced Tumor Antigen Assembly for Enhanced Effector CD8+ T Cell Activation

The activation of tumor‐specific effector immune cells is key for successful immunotherapy and vaccination is a powerful strategy to induce such adaptive immune responses. However, the generation of effective anticancer vaccines is challenging. To overcome these challenges, a novel straight‐forward strategy of adjuvant‐induced tumor antigen assembly to generate nanovaccines with superior antigen/adjuvant loading efficiency is developed. To protect nanovaccines in circulation and to introduce additional functionalities, a biocompatible polyphenol coating is installed. The resulting functionalizable nanovaccines are equipped with a pH (low) insertion peptide (pHLIP) to facilitate endolysosomal escape and to promote cytoplasmic localization, with the aim to enhance cross‐presentation of the antigen by dendritic cells to effectively activate CD8⁺ T cell. The results demonstrate that pHLIP‐functionalized model nanovaccine can induce endolysosomal escape and enhance CD8⁺ T cell activation both in vitro and in vivo. Furthermore, based on the adjuvant‐induced antigen assembly, nanovaccines of the clinically relevant tumor‐associated antigen NY‐ESO‐1 are generated and show excellent capacity to elicit NY‐ESO‐1‐specific CD8⁺ T cell activation, demonstrating a high potential of this functionalizable nanovaccine formulation strategy for clinical applications.     

Dual‐Stage Light Amplified Photodynamic Therapy against Hypoxic Tumor Based on an O2 Self‐Sufficient Nanoplatform

Tumor hypoxia severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a liposome‐based nanoparticle (designated as LipoMB/CaO₂) with O₂ self‐sufficient property for dual‐stage light‐driven PDT is demonstrated to address this problem. Through a short time irradiation, ¹O₂ activated by the photosensitizer methylene blue (MB) can induce lipid peroxidation to break the liposome, and enlarge the contact area of CaO₂ with H₂O, resulting in accelerated O₂ production. Accelerated O₂ level further regulates hypoxic tumor microenvironment and in turn improves ¹O₂ generation by MB under another long time irradiation. In vitro and in vivo experiments also demonstrate the superior competence of LipoMB/CaO₂ to alleviate tumor hypoxia, suppress tumor growth and antitumor metastasis with low side‐effect. The O₂ self‐sufficient LipoMB/CaO₂ nanoplatform with dual‐stage light manipulation is a successful attempt for PDT against hypoxic tumor.     

Nanoparticle‐Enhanced Radiotherapy to Trigger Robust Cancer Immunotherapy

External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing‐radiation beams. However, the efficacy of radiotherapy is usually limited by tumor hypoxia‐associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core–shell nanoparticles based poly(lactic‐co‐glycolic) acid (PLGA) are fabricate, by encapsulating water‐soluble catalase (Cat), an enzyme that can decompose H₂O₂ to generate O₂, inside the inner core, and loading hydrophobic imiquimod (R837), a Toll‐like‐receptor‐7 agonist, within the PLGA shell. The formed PLGA‐R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune‐suppressive tumor microenvironment. The tumor‐associated antigens generated postradiotherapy‐induced immunogenic cell death in the presence of such R837‐loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next‐generation radiotherapy strategy to enable synergistic whole‐body therapeutic responses after local treatment, greatly promising for clinical translation.     

Platelet Membrane‐Camouflaged Magnetic Nanoparticles for Ferroptosis‐Enhanced Cancer Immunotherapy

Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe₃O₄‐SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non‐inflamed tumors for cancer immunotherapy. Fe₃O₄‐SAS@PLT are built from sulfasalazine (SAS)‐loaded mesoporous magnetic nanoparticles (Fe₃O₄) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate‐cystine antiporter system X_c^? pathway. Fe₃O₄‐SAS @ PLT‐mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe₃O₄‐SAS @ PLT‐mediated ferroptosis could not only induce tumor‐specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe₃O₄‐SAS @ PLT‐mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.     

Fe(III)-Naphthazarin Metal–Phenolic Networks for Glutathione-Depleting Enhanced Ferroptosis–Apoptosis Combined Cancer Therapy

Nowadays, Fenton chemistry-based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H₂O₂ into cytotoxic hydroxyl radicals (·OH). However, the elimination of ·OH by intracellular overexpressed glutathione (GSH) results in unsatisfactory antitumor efficiency. In addition, the single mode of consuming GSH and undesirable drug loading efficiency cannot guarantee the efficient cancer cells killing effect. Herein, a simple one-step strategy for the construction of Fe³⁺-naphthazarin metal–phenolic networks (FNP MPNs) with ultrahigh loading capacity, followed by the modification of NH₂-PEG-NH₂, is developed. The carrier-free FNP MPNs can be triggered by acid and GSH, and rapidly release naphthazarin and Fe³⁺, which is further reduced to Fe²⁺ that exerts Fenton catalytic activity to produce abundant ·OH. Meanwhile, the Michael addition between naphthazarin and GSH can lead to GSH depletion and thus achieve tumor microenvironment (TME)-triggered enhanced CDT, followed by activating ferroptosis and apoptosis. In addition, the reduced Fe²⁺ as a T₁-weighted contrast agent endows the FNP MPNs with magnetic resonance imaging (MRI) functionality. Overall, this work is the debut of naphthazarin as ligands to fabricate functional MPNs for effectively depleting GSH, disrupting intracellular redox homeostasis, and enhancing CDT effects, which opens new perspectives on multifunctional MPNs for tumor synergistic therapy.     

Pulmonary Codelivery of Doxorubicin and siRNA by pH‐Sensitive Nanoparticles for Therapy of Metastatic Lung Cancer

A pulmonary codelivery system that can simultaneously deliver doxorubicin (DOX) and Bcl2 siRNA to the lungs provides a promising local treatment strategy for lung cancers. In this study, DOX is conjugated onto polyethylenimine (PEI) by using cis‐aconitic anhydride (CA, a pH‐sensitive linker) to obtain PEI‐CA‐DOX conjugates. The PEI‐CA‐DOX/siRNA complex nanoparticles are formed spontaneously via electrostatic interaction between cationic PEI‐CA‐DOX and anionic siRNA. The drug release experiment shows that DOX releases faster at acidic pH than at pH 7.4. Moreover, PEI‐CA‐DOX/Bcl2 siRNA complex nanoparticles show higher cytotoxicity and apoptosis induction in B16F10 cells than those treated with either DOX or Bcl2 siRNA alone. When the codelivery systems are directly sprayed into the lungs of B16F10 melanoma‐bearing mice, the PEI‐CA‐DOX/Bcl2 siRNA complex nanoparticles exhibit enhanced antitumor efficacy compared with the single delivery of DOX or Bcl2 siRNA. Compared with systemic delivery, most drug and siRNA show a long‐term retention in the lungs via pulmonary delivery, and a considerable number of the drug and siRNA accumulate in tumor tissues of lungs, but rarely in normal lung tissues. The PEI‐CA‐DOX/Bcl2 siRNA complex nanoparticles are promising for the treatment of metastatic lung cancer by pulmonary delivery with low side effects on the normal tissues.     

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors

Regulating the tumor microenvironment (TME) has been a promising strategy to improve antitumor therapy. Here, a red blood cell membrane (mRBC)‐camouflaged hollow MnO₂ (HMnO₂) catalytic nanosystem embedded with lactate oxidase (LOX) and a glycolysis inhibitor (denoted as PMLR) is constructed for intra/extracellular lactic acid exhaustion as well as synergistic metabolic therapy and immunotherapy of tumor. Benefiting from the long‐circulation property of the mRBC, the nanosystem can gradually accumulate in a tumor site through the enhanced permeability and retention (EPR) effect. The extracellular nanosystem consumes lactic acid in the TME by catalyzing its oxidation reaction via LOX. Meanwhile, the intracellular nanosystem releases the glycolysis inhibitor to cut off the source of lactic acid, as well as achieve antitumor metabolic therapy through the blockade of the adenosine triphosphate (ATP) supply. Both the extracellular and intracellular processes can be sensitized by O₂, which can be produced during the decomposition of endogenous H₂O₂ catalyzed by the PMLR nanosystem. The results show that the PMLR nanosystem can ceaselessly remove lactic acid, and then lead to an immunocompetent TME. Moreover, this TME regulation strategy can effectively improve the antitumor effect of anti‐PDL1 therapy without the employment of any immune agonists to avoid the autoimmunity.     

Six Birds with One Stone: Versatile Nanoporphyrin for Single-Laser-Triggered Synergistic Phototheranostics and Robust Immune Activation

Simultaneous photodynamic therapy (PDT) and photothermal therapy (PTT) can reduce the risks of drug leakage, body burden, and preparation complexity in traditional combination PDT/PTT. Here, a versatile nanoporphyrin (Pp18-lipos) self-assembled from lipid–purpurin 18 conjugates (Pp18-lipids) and pure lipids is presented. The as-prepared Pp18-lipos with 2 mol% Pp18-lipids can perform effective PDT and fluorescence imaging. The Pp18-lipos with 65 mol% Pp18 can perform potent PTT and photoacoustic imaging. The chelation of Mn²⁺ endows the Pp18-lipids-Mn²⁺ a high T₁-weighted magnetic resonance imaging contrast. Notably, pretreatment of low-dose PDT facilitates the endocytosis and tumor accumulation of Pp18-lipos, thus achieving synergistic PDT/PTT. Upon exposure to a single 705 nm-laser, the combination of PDT/PTT achieves a significantly higher tumor growth inhibition rate than PDT or PTT alone. In addition, it is found that the synergistic PDT/PTT triggers more potent anti-tumor immune response including tumor infiltration of immune cells and release of related cytokines.     

Facile synthesis by a covalent binding reaction for pH‐responsive drug release of carboxylated chitosan coated hollow mesoporous silica nanoparticles

In this study, a promising drug nano‐carrier system consisting of mono‐dispersed and pH sensitive carboxylated chitosan‐hollow mesoporous silica nanoparticles (Ccs‐HMSNs) suitable for the treatment of malignant cells was synthesised and investigated. At neutral pH, the Ccs molecules are orderly aggregated state, which could effectively hinder the release of loaded drug molecules. However, in slightly acidic environment, Ccs chains are heavily and flexibly entangled in gel state, which would enhance the subsequent controlled release of the loaded drug. Using doxorubicin hydrochloride (DOX•HCl) as the drug model, their results demonstrated that the system had an excellent loading efficiency (64.74 μg/mg Ccs‐HMSNs) and exhibited a pH‐sensitive release behaviour. Furthermore, confocal laser scanning microscopy revealed that the Ccs‐HMSNs nanocomposite could effectively deliver and release DOX•HCl to the nucleus of HeLa cells, thereby inducing apoptosis. In addition, MTT assay also confirmed that DOX•HCl loaded Ccs‐HMSNs (DOX•HCl@Ccs‐HMSNs) exhibited a good anticancer effect on HeLa cells with a time‐dependent manner. Finally, haemolysis experiment showed Ccs‐HMSNs had no haemolytic activity at all the tested concentrations (5–320 μg/mL). Thus, this biocompatible and effective nano‐carrier system will have potential applications in controllable drug delivery and cancer therapy.Inspec keywords: drug delivery systems, mesoporous materials, silicon compounds, nanoparticles, nanocomposites, nanofabrication, drugs, nanomedicine, biomedical materials, pH, aggregation, gels, optical microscopy, cellular biophysics, cancer, filled polymersOther keywords: facile synthesis, covalent binding reaction, pH‐responsive drug release, carboxylated chitosan coated hollow mesoporous silica nanoparticles, drug nanocarrier system, monodispersed carboxylated chitosan‐hollow mesoporous silica nanoparticles, pH sensitive carboxylated chitosan‐hollow mesoporous silica nanoparticles, malignant cell treatment, neutral pH, orderly aggregated state, loaded drug molecules, acidic environment, gel state, doxorubicin hydrochloride, drug model, confocal laser scanning microscopy, nanocomposite, HeLa cells, apoptosis, MTT assay, anticancer effect, haemolysis experiment, biocompatible nanocarrier system, drug delivery, cancer therapy, SiO₂