Recent years have witnessed incredible growth in RNA therapeutics, which has benefited significantly from decades of research on lipid nanoparticles, specifically its key component-the ionizable lipid. This comment discusses the major ionizable lipid types, and provides perspectives for future development. Need for ionizable lipidsBroadly speaking, ribonucleic acid (RNA) therapeutics include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs), and single-guide RNAs (sgRNAs)-mediated CRISPR-Cas9 system, which can manipulate essentially any gene of interest through distinct modes of action 1 . However, RNA therapeutics are susceptible to nucleases and cannot permeate cells due to their large size and negative charge. Delivery of RNAs to target cells by clinically translatable lipid nanoparticles (LNPs) provides vast opportunities to tackle a series of life-threatening diseases including COVID-19 2 . LNPs typically consist of four components-ionizable lipid, phospholipid, cholesterol, and PEGylated lipid, among which, the ionizable lipid plays a major role in protecting RNAs and facilitating their cytosolic transport. Ionizable lipids are positively charged at acidic pH to condense RNAs into LNPs, but are neutral at physiological pH to minimize toxicity. They can be protonated in the acidic endosome after cellular uptake, and interact with anionic endosomal phospholipids to form cone-shaped ion pairs that are not compatible with a bilayer (Fig. 1). These cationicanionic lipid pairs drive the transition from the bilayer structure to the inverted hexagonal H II phase, which facilitates membrane fusion/disruption, endosomal escape and cargo release into the cytosol 3 . Since 2008, ionizable lipids with diverse chemical identities have been created. Systematic categorization of these lipids based on their structures can greatly benefit the field and facilitate the development of next-generation ionizable lipids. Currently, there are five major ionizable lipid types that are widely used for RNA delivery (Fig. 1). Unsaturated ionizable lipidsTail saturation greatly influences the fluidity and delivery efficiency of ionizable lipids. Increasing the tail unsaturation from 0 to 2 cis double bonds correlates with an increased tendency for bilayer lipids to form a nonbilayer phase 4 , leading to enhanced membrane disruption and

Photodynamic therapy (PDT) is a promising anticancer treatment and is clinically approved for different types of tumors. However, current PDT suffers several obstacles, including its neutralization by excess glutathione (GSH) in the tumor tissue and its strongly proangiogenic tumor response. In this work, a biomimic, multifunctional nanoparticle‐based PDT agent, combining a tumor‐targeted photosensitizer with GSH scavenging and antiangiogenesis therapy, is developed. A porphyrinic Zr–metal–organic framework nanoparticle is used simultaneously as the photosensitizer and the delivery vehicle of vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor apatinib. The core nanoparticles are wrapped in MnO2 to consume the intratumoral GSH and then decorated with a tumor cell membrane camouflage. After intravenous administration, the nanoparticles selectively accumulate in tumor through homotypic targeting mediated by the biomimic decoration, and the combination of enhanced PDT and antiangiogenic drug significantly improves their tumor inhibition efficiency. This study provides an integrated solution for mechanism‐based enhancement of PDT and demonstrates the encouraging potential for multifunctional nanosystem applicable for tumor therapy.

Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.