Fluffy hybrid nanoadjuvants for reversing the imbalance of osteoclastic andosteogenic niches in osteoporosis

Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite thedevelopment of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their lowbioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. Thiscalls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybridstructures with bioactive components and stable fluffy topological morphology by cross-linking calcium andphosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequentgrafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealedthat these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecularmechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that smalldoseAL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivoresults restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as theconsequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant withpeculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well asbone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies forother bone diseases.

Chiral polypeptide nanoparticles as nanoadjuvants of nanovaccines for efficient cancer prevention and therapy

The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of chiral polypeptides,poly(L-phenylalanine)-block-poly(L-lysine)(PL-K)and poly(Lphenylalanine)-block-poly(D-lysine)(PD-K),were synthesized and used as nanoadjuvants of nanovaccines for cancer prevention and therapy.The amphiphilic polypeptides self-assembled into nanoparticles with a diameter of about 30 nm during ultrasonic-assisted dissolution in phosphate-buffered saline.The nanovaccines PL-K-OVA and PD-K-OVA were easily prepared by mixing solutions of PL-K or PD-K and the model antigen chicken ovalbumin(OVA),respectively,with loading efficiencies of almost 100%.Compared to PL-K-OVA,PD-K-OVA more robustly induced dendritic cell maturation,antigen cross-presentation,and adaptive immune response.More importantly,it effectively prevented and treated the OVA-expressed B16-OVA melanoma model.PD-K-OVA achieved a tumor inhibition rate of 94.9%and even 97.0%by combining with anti-PD-1 antibody.Therefore,the chiral polypeptide nanoparticles represent simple,efficient,and extensively applicable nanoadjuvants for various nanovaccines.

Immunologically effective poly(D-lactic acid) nanoparticle enhances anticancer immune response

Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lactic acid)(PLA)nanoparticle as an efficient nanoadjuvant to activate adaptive anticancer immunity.Two chiral nanovaccines were prepared by directly mixing amino-terminated PLA(PLLA-NH2 or PDLA-NH2)with the model protein antigen ovalbumin(OVA).After being injected into mice subcutaneously,both nanovaccines efficiently migrated to the lymph nodes to initiate the sequential anticancer immune responses.Compared with the PLLA nanovaccine(PLLA-OVA),the PDLA one(PDLA-OVA)contributed to more robust dendritic cell(DC)maturation,antigen presentation,and T lymphocyte activation.In addition to the activation of cellular immunity,PDLA-OVA also triggered a more vigorous activation of humoral immunity,which induced the production of more anti-OVA immunoglobulin G(IgG)than PLLA-OVA.When used as prophylactic or therapeutic nanovaccine toward murine melanoma models,PDLA-OVA triggered more potent adaptive anticancer immune responses that more effectively inhibited the cancer genesis and progression,indicating the significant potential of immunologically effective PDLA nanoadjuvant in cancer immunotherapy.