Nanocarriers have therapeutic potential to facilitate drug delivery, including biological agents, small-molecule drugs, and nucleic acids. However, their efficiency is limited by several factors; among which, endosomal/lysosomal degradation after endocytosis is the most important. This review summarizes advanced strategies for overcoming endosomal/lysosomal barriers to efficient nanodrug delivery based on the perspective of cellular uptake and intracellular transport mechanisms. These strategies include promoting endosomal/lysosomal escape, using non-endocytic methods of delivery to directly cross the cell membrane to evade endosomes/lysosomes and making a detour pathway to evade endosomes/lysosomes. On the basis of the findings of this review, we proposed several promising strategies for overcoming endosomal/lysosomal barriers through the smarter and more efficient design of nanodrug delivery systems for future clinical applications.

The iron oxide nanoparticles (IONPs), possessing both magnetic behavior and semiconductor property, have been extensively used in multifunctional biomedical fields due to their biocompatible, biodegradable and low toxicity, such as anticancer, antibacterial, cell labelling activities. Nevertheless, there are few IONPs in clinical use at present. Some IONPs approved for clinical use have been withdrawn due to insufficient understanding of its biomedical applications. Therefore, a systematic summary of IONPs’ preparation and biomedical applications is crucial for the next step of entering clinical practice from experimental stage. This review summarized the existing research in the past decade on the biological interaction of IONPs with animal/cells models, and their clinical applications in human. This review aims to provide cutting-edge knowledge involved with IONPs’ biological effects in vivo and in vitro, and improve their smarter design and application in biomedical research and clinic trials. Graphical Abstract

Calcium phosphate nanoparticles represent promising materials for drug delivery because of its favorable properties, including biocompatibility, biodegradability and strong affinity for binding to nucleic acids (pDNA, siRNA, miRNA, etc.) and therapeutic drugs (cisplatin, carboplatin, paclitaxel, gefitinib, doxorubicin, etc.). Various strategies to prepare the size-controllable, stable, targeting and pH-responsive CaP nanocarriers have been extensively developed as the potential candidates in clinic. This review discusses the mostly recent developments in the design of calcium phosphate nanocarriers as drug delivery systems and therapeutic agents. Additionally, the advantage is unquestionably demonstrated and the obstacles are thoroughly examined in order to overcome future clinical issues.

Pulmonary Fibrosis (PF) is a fatal disease in the interstitial lung associated with high mortality, morbidity, and poor prognosis. Transforming growth factor-β1 (TGF-β1) is a fibroblast-activating protein that promotes fibrous diseases. Herein, an inhalable system was first developed using milk exosomes (M-Exos) encapsulating siRNA against TGF-β1 (MsiTGF-β1), and their therapeutic potential for bleomycin (BLM)-induced PF was investigated. M-siTGF-β1 was introduced into the lungs of mice with PF through nebulization. The collagen penetration effect and lysosomal escape ability were verified in vitro. Inhaled MsiTGF-β1 notably alleviated inflammatory infiltration, attenuated extracellular matrix (ECM) deposition, and increased the survival rate of PF mice by 4.7-fold. M-siTGF-β1 protected lung tissue from BLM toxicity by efficiently delivering specific siRNA to the lungs, leading to TGF-β1 mRNA silencing and epithelial mesenchymal transition pathway inhibition. Therefore, M-siTGF-β1 offers a promising avenue for therapeutic intervention in fibrosis-related disorders.

The insufficient infiltration and functional inhibition of CD8⁺ T cells due to tumor microenvironment (TME) are considered enormous obstacles to anti‐tumor immunotherapy. Herein, a pH‐responsive core‐shell manganese phosphate nanomodulator co‐loading siPD‐L1 and Mn²⁺ into nanoparticles coated with hyaluronic acid was prepared, which was aimed at the bidirectional reprogramming the tumor microenvironment: (1) “Brakes off,” restoring CD8⁺ T cells function by siPD‐L1 knockdowning PD‐L1 expression of tumor cells; (2) “Step on the accelerator,” promoting CD8⁺ T cells infiltration in tumors tissue based on the multidimensional immune effects of Mn²⁺ (immunogenic cell death induced the enhancing cGAS‐STING pathway, the proliferation and maturation of relative immune cells). Additionally, this strategy could induce macrophage polarization and inhibit the regulatory T cells in tumor site. This work provided a manganese phosphate nanomodulator to reprogram the immune TME for an enhanced comprehensive anti‐tumor effect of triple negative breast cancer, which offers a robust method for tumor immunotherapy in future clinical applications.

The integration of high strength, super toughness, damage resistance, body-temperature shape memory, and biosafety into a single skin-mimic material system has been a notable challenge in the realm of material science and biomedical applications. In this study, “Lego-like” polyurethane (PU) was selected to amalgamate multiple properties through the design of multilevel structures. By comprehensively designing the chemical and sequence structures of blocks, coordinating weak/strong hydrogen bonds, and achieving rational microphase separation and crystallization, an elastomer was obtained with an exceptional true tensile strength of 1.42 gigapascal, a high fracture energy of 384.7 ± 18.9 kJ/m ² , and a skin-like nonlinear mechanoresponse. The coordination of crystallization and physical cross-linking also guaranteed excellent body-temperature shape memory properties, which are applicable in 4D printing. Moreover, the obtained elastomer is biosafe and has the potential to promote cell proliferation and DNA repair, which will find wide applications in the biomedical field including minimally invasive surgery.