Dendritic cell (DC) vaccines have made substantial progress in cancer immunotherapy; however, their efficacy is still limited by the transient in vivo fate of mature DCs and suboptimal lymphatic transport. Here, we report a metabolically glycoengineered, nanovesicle-based and personalized nanovaccine (GSNVs) that displays upregulated C-C chemokine receptor 7 (CCR7) and major histocompatibility (MHC)-I complexes to promote lymph node homing and effectively presents tumor antigens to CD8⁺ T cells, ultimately triggering a strong antigen-specific antitumor immune response. GSNVs were generated from ManNAc-engineered bone marrow-derived DCs (BMDCs) pulsed with highly immunogenic exosomes derived from senescent tumor cells. Metabolic glycoengineering endows BMDCs with enhanced antigen cross-presentation, elevated CCR7 expression, and negligible PD-L1 levels, thereby promoting robust and persistent CD8⁺ T cell responses. Notably, GSNVs treatment elicits robust antitumor immunity, rescues T cell exhaustion, and markedly inhibits tumor growth of B16-OVA-bearing mice. Collectively, these results reveal that our metabolically glycoengineered GSNVs could be an effective strategy to overcome the inherent limitation of DC vaccines in inducing adaptive antitumor immunity for its potential application in personalized cancer immunotherapy.

Invasive pulmonary fungal diseases (IPFD) represent a growing global health crisis, with escalating incidence and mortality rates, posing a particularly life-threatening risk to immunocompromised populations. The complexity of diagnosis, limited therapeutic options, and the growing challenge of antifungal resistance have significantly constrained the clinical efficacy, leading to poor patient outcomes. Recently, the integration of revolutionary drug delivery platforms with classical antifungal agents, such as optimized nebulized amphotericin B, voriconazole-loaded liposomes and inhalable amphotericin B microspheres, has demonstrated significant clinical potential, particularly in pulmonary applications, by markedly enhancing biodistribution at the infection site while substantially minimizing systemic adverse effects. This comprehensive review synthesized recent advances in IPFD research, encompassing epidemiological characteristics, molecular pathogenesis, clinical manifestations, cutting-edge diagnostic technologies (including advanced imaging, fungal-specific biomarkers and molecular techniques like polymerase chain reaction (PCR) and next-generation sequencing) as well as formulation-based therapeutics that optimize pulmonary targeting to improve efficacy and reduce systemic toxicity. This review aimed to provide insights for the future development of precision-targeted delivery mechanisms and next-generation antifungal agents.

Photodynamic therapy (PDT) employs lasers to activate photosensitizers, generating reactive oxygen species (ROS) for tumor cell destruction. However, the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency. Recent studies have shown that lysosome-targeted PDT can directly disrupt the “explosive depot” of tumor cells by triggering the release of abundant hydrolases from lysosomes. Nevertheless, existing lysosome-targeted strategies rely predominantly on a single protonation mechanism, resulting in low targeted efficiency. To enhance lysosome-targeted bursting, this study adopted a dual-mode recognition strategy, combining “hydrophobic interaction-aided fusion” with “charge-directed anchoring”. Specifically, pyropheophorbide-a (PPa) was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths (C1, C4, C8, and C12), yielding lysosome-targeted bursting photosensitizers (PPa1, PPa4, PPa8, and PPa12). Self-assembled nanoparticles (LPPa NPs) were then prepared to facilitate tumor delivery. The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency, lysosomal targeted capability, and assembly stability of LPPa NPs. Notably, PPa4 NPs demonstrated superior cellular uptake, enhanced ROS generation, and effective lysosome-targeted bursting, thereby markedly improving antitumor efficacy. In summary, the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.

Larotaxel (LTX), a next-generation taxane chemotherapeutic agent, demonstrates broad-spectrum antitumor activity and enhanced efficacy against resistant cancers compared to paclitaxel in clinical studies. To overcome delivery challenges and exploit the tumor microenvironment, LTX was conjugated via disulfide bonds to 2-hydroxy-1,3-bis(alkanoyl) glyceride to form prodrugs with different fatty acid chain lengths of triglyceride, LTX-SS-TG(C8) and LTX-SS-TG(C16). These dual-stimuli responsive prodrugs were designed for rapid, complete LTX release triggered by elevated glutathione (GSH) and lipase activity within tumors. Albumin is considered as an ideal drug carrier due to its biocompatibility and ligand-binding domains. We co-assembled the prodrugs with albumin and optimized the nanoparticle formation. Our findings revealed that alkanoyl chain length critically governed prodrug-albumin binding affinity, and improved the in vivo pharmacokinetic profile of nanoparticles. Specifically, the LTX-SS-TG(C16) NPs demonstrated superior albumin assembly, resulting in nanoparticles with an area under the curve (AUC) 12.99 times higher than that of the LTX solution. And these nanoparticles achieved improved tumor-specific distribution, potent antitumor efficacy, and significantly improved safety. This study provides a novel strategy for optimizing LTX delivery via albumin-based prodrug nanoparticles, broadening its potential for clinical application.

Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines. These prodrugs typically consist of drug modules, response modules, and modification modules. The general role of modification modules is to modulate the self-assembly ability of the prodrugs. How to optimize the structure of modification modules for balanced efficacy and safety of high-toxicity chemotherapeutic drugs deserves to be further investigated. In this study, a modification strategy of aliphatic alcohols with various chain lengths (SC₄, SC₈, SC₁₂, SC₁₆ and SC₂₀) was carried out to design five cabazitaxel (CBZ) prodrugs. Among them, CBZ-SC NPs with shorter chain length (SC₄ and SC₈) showed poor self-assembly stability. CBZ-SC₁₂ NPs also failed to remain stable while the other two CBZ-SC NPs exhibited good stability. In turn, the drug release rate was hindered by the increasing chain length. CBZ-SC₁₂ NPs caused kidney damage due to their high redox-sensitivity and rapid release rate during circulation. By contrast, CBZ-SC NPs with longer chain length (SC₁₆ and SC₂₀) not only demonstrated superior stability with improved pharmacokinetic behavior, but also might solve the dilemma of dose-related toxicity caused by CBZ. Overall, these findings emphasized the importance of chain length in modification module to modulate the efficacy and safety of CBZ prodrug nanoassemblies.

Dimeric prodrug nanoassemblies (DPNAs) offer great potential in improving the efficacy of chemotherapy. Previously, we developed tetrasulfide bonds as a novel response module and the obtained γ-4S-2CTX NPs demonstrated superlative self-assembly stability and enhanced anti-tumor efficacy. However, current DPNAs mainly rely on simple PEGylation for surface modification to improve blood circulation, which lacks tumor-selective functionality and limits their further application. To address these limitations, we introduced a new surface modification strategy using RM-1 tumor cell membranes (CMs) to enhance biofunctionality. The initial attempt to use CMs as a single surface modification failed because the affinity of nanocores-CMs remains a problem, which affected the stability of membrane-coated DPNAs. To address this, we used 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethyleneglycol)-2000] (DSPE-PEG_2k) as an adhesive bridge to improve the affinity between CMs and DPNAs, resulting in a dual-modified formulation termed CM-pDPNAs. This dual modification strategy enhanced CMs binding to DPNAs, enabling precise tumor recognition and internalization, thereby improving tumor elimination efficacy. Furthermore, this approach addressed key challenges associated with current CM-coated nanoparticles (CM-NPs), including complex preparation procedures and poor drug-carrier compatibility. This work elucidates the application of CMs as surface modification modules, paving the way for the next generation of biomimetic prodrug nanoassemblies with superior stability and tumor specificity.

The tumor microenvironment-sensitive prodrug-based nanoparticles (NPs) have emerged as a promising drug delivery system (DDS). The shape of these particles plays a crucial role in their in vivo behavior. However, non-spherical organic NPs are rarely reported due to the inherent flexibility and variability of organic molecules. Herein, we fabricate reduction-sensitive prodrug NPs and explore the impact of their morphology properties on their in vivo fate. Prodrugs are self-assembled into spherical NPs with distearoyl phosphoethanolamine-PEG2000 (DSPE-PEG_2K), or into rod-shaped NPs with D-α-tocopherol polyethylene glycol 2000 succinate (TPGS_2K) due to the stronger binding energy. In comparison with spherical NPs, the endocytosis of rod-shaped NPs predominantly relies on caveolae-mediated pathways rather than clathrin-mediated ones, potentially avoiding degradation by lysosomes. Additionally, the rod-shaped NPs exhibit prolonged circulation time, increased tumor accumulation, and enhanced antitumor ability. Our current findings reveal the significant effect of particle shape on the behavior of prodrug NPs and introduce a novel paradigm for high-efficacy cancer therapy of prodrug NPs.

During the development of leukemia, the overgrowth of leukemia cells in the bone marrow transforms the normal hematopoietic microenvironment into the leukemia microenvironment which favors its growth and inhibits normal hematopoietic stem cells. The leukemia microenvironment exhibits abnormalities in redox substances, metabolism, immune response, mesenchymal cells, extracellular matrix, stromal cells, hypoxia, and more. These factors collectively provide a shelter for the malignant proliferation of leukemia cells. Recently, as the understanding of the leukemia microenvironment deepens, targeting or remodeling the abnormal leukemia microenvironment is becoming an effective strategy for leukemia treatment. Nanomedicine technology can effectively change pharmacokinetic profiles, thus demonstrating many advantages in modulating the leukemia microenvironment and improving therapeutic selectivity. In this review, we outline the characteristics of abnormal leukemia bone marrow microenvironment, focusing on the abnormal changes in the redox, metabolic and immune microenvironment. We also summarize emerging nanotechnology strategies in remodeling or targeting the aforementioned abnormal microenvironment. In addition, the unique advantages and bright prospects of nanotechnology in remodeling and targeting the leukemia microenvironment are discussed.