Messenger ribonucleic acid (mRNA)-based therapeutics hold great prospects in disease treatment and lipid nanoparticles (LNPs) are the most extensively applied non-viral platform for RNA delivery in clinics. Despite the clinical success of LNPs as vehicles have been achieved, developing LNPs with enhanced mRNA transmembrane delivery and transfection efficiency in a non-toxic manner is highly desirable and challenging. In this study, we designed a series of new ionizable amino lipids with piperazine-derived headgroups and constructed a group of LNPs to promote the transfection activity of mRNA cargos. Among them, LNP formulated with lipid 10 (L10-LNP) can efficiently package mRNA and perform superior transfection efficiency both in vitro and in vivo, which is mainly attributed to the improved intracellular uptake and effective endosomal escape. We verified that a single administration of L10-LNP packaging interleukin (IL)-12 mRNA induced tumor shrink and even regression by robust activation of immune effector CD8⁺ T cells and stimulating the generation of IFN-γ without causing systemic toxicity, which provides a promising platform for clinical cancer immunotherapy.

Transdermal drug delivery is an appealing option except for oral and hypodermic administration. With the advancement of skin penetration strategies, various anticancer therapeutics ranging from lipophilic small-molecule drugs to hydrophilic biomacromolecules, can be administered transdermally, offering an optional regimen to treat skin cancers. In addition, the activation of the skin immune systems can also assist the treatment of distal sites. Current approaches on enhancing the transdermal delivery efficacy of anticancer drugs are summarized in this review. We also survey recent advances in micro- and nanotechnology-based transdermal formulations for cancer treatment, such as chemotherapy, gene therapy, immunotherapy, phototherapy and combination therapy. New penetration enhancers, materials, formulations and their hypothesized mechanisms for transdermal delivery are highlighted. Advantages and limitations regarding the state-of-the-art transdermal delivery technologies, as well as future perspective are also discussed.