Driven by recent successful clinical translation, nucleic acid therapeutics are being actively investigated to expand their applications to various diseases, including renal genetic disorders. As life expectancy increases and the burden of renal diseases continues to rise, nucleic acid therapeutics are considered promising alternatives to conventional treatments. This review summarizes key considerations in the design and fabrication of nanocarriers for the systemic delivery of nucleic acid therapeutics to the kidneys. Key aspects of the renal microenvironment are discussed to guide the design of nanocarriers, including conjugates and nanoparticles. This review also covers renal genetic disorders and nucleic acid-based treatment approaches, including small interfering RNAs (siRNAs), clustered regularly interspaced short palindromic repeats (CRISPR) systems, and messenger RNA (mRNA) therapeutics. In particular, recent strategies for kidney-targeted nanocarriers are highlighted, with an emphasis on their efficacy, challenges, and limitations. Perspectives on the design of nanocarriers for systemic nucleic acid delivery to the kidneys are also provided, offering insights into potential therapeutic approaches for renal genetic disorders.
Nucleic acid therapeutics offer unique opportunities to develop personalized precision therapies by responding specifically and effectively at the gene level to evolving pathogens. However, many nucleic acid drugs employ a single-target strategy, which is effective in monogenic disorders, yet can be ineffective in treating diseases characterized by complex and interacting molecular events. Nucleic acid combinations capable of simultaneously modulating multiple pathways and harnessing concerted effects constitute a promising approach to combatting complex, dynamically evolving and heterogeneous diseases. Here, we report a combination strategy utilizing small activating RNA to activate tumor suppressor genes alongside small interfering RNA to silence oncogenes for therapeutic potential and clinical relevance in cancer treatment using patient-derived tumor models of pancreatic cancer. Transcriptomic and proteomic profiling of individual patient tumors enabled rational design of patient-specific combinations, which exhibited superior anticancer efficacy through coordinated regulation of multiple genes. Importantly, diverse combinations were tailored to individual patient tumor models to elicit therapeutic responses, while certain specific combinations demonstrated therapeutic efficacy across different tumor models that shared similar genetic features, highlighting the flexibility and pan-treatment potential. Our findings not only confirm the efficacy of the combination approach for cancer treatment, but also underscore its potential applicability to other complex malignancies.
Nucleic acid aptamers are single-stranded oligonucleotides that recognize diverse molecular targets with high affinity and specificity. Owing to their small size, amenability to chemical synthesis, and facile functionalization, aptamers are emerging as versatile alternatives or complements to antibodies in pharmaceutical sciences. This review summarizes recent advances from 2020 to 2025 in the pharmaceutical applications of aptamers, focusing on four areas: therapeutics, biosensing, bioanalysis, and process analysis. In therapeutics, the U.S. Food and Drug Administration (FDA) approval of Izervay (avacincaptad pegol) in 2023 marked a significant milestone, renewing interest in aptamer-based drug development. Aptamers are being explored for cancer therapy, immunotherapy, and neurodegenerative disease treatment, with several candidates in clinical trials. In diagnostics, aptamer-based biosensors (aptasensors) enable sensitive detection of tumor markers, disease biomarkers, and infectious disease agents, demonstrating particular utility in point-of-care applications. For bioanalysis of biopharmaceuticals, anti-idiotype aptamers serve as capture molecules for antibody drug quantification, offering advantages in batch-to-batch consistency and stability. In process analytical technology, aptamers are being applied to real-time monitoring of cell culture conditions and quality control of antibody drug manufacturing. These advances position nucleic acid aptamers as increasingly important tools in pharmaceutical sciences.
Gapmer-type antisense oligonucleotides (Gapmers) are promising therapeutic agents. However, their clinical potential is frequently limited by off-target toxicities. To address this issue, Gapmers have been optimized by modifying the ribose moiety or internucleotide linkage, but toxicity has not always been reduced. The toxicity is due to the unintended interactions between the ribose-type modified nucleic acids with phosphorothioate backbones and the endogenous proteins. We therefore hypothesized that the use of acyclic nucleic acids, which possess an entirely distinct structure to ribose, would solve the aforementioned issue. In this study, we demonstrate that the incorporation of an acyclic analog, serinol nucleic acid (SNA) or L-threoninol nucleic acid (L-aTNA), provides an alternative approach. Notably, substitution with SNA or L-aTNA effectively mitigated toxicity, even when conventional 2'-O-methyl modification was unsuccessful. This approach reduced cytotoxicity across multiple Gapmer sequences and designs in a position-dependent manner. Mechanistically, our investigation into these acyclic nucleic acids revealed that reduced toxicity was associated with suppression of P54nrb protein mislocalization. Furthermore, representative SNA- or L-aTNA-modified Gapmers exhibited markedly reduced hepatotoxicity in vivo. Collectively, these findings suggest that acyclic nucleic acids have potential as a useful chemical strategy for the development of safer Gapmer therapeutics.
Nucleic acid therapeutics, including oligonucleotides, messenger RNA and DNA, are promising drug modalities for treating various diseases. However, despite their increasing impact on medicine, their precise and efficient delivery remains a considerable challenge. Dendrimers, recognized by their uniquely branched architecture and precise structures in concert with cooperative multivalency, are a platform for targeted and precise delivery of nucleic acid therapeutics. Here we review state-of-the-art engineering of dendrimers pertaining to nucleic acid delivery, highlighting progress made in their design and functional mechanization for delivering different types of nucleic acids for therapeutic applications. We also discuss challenges including manufacturing, safety and regulatory issues associated with their clinical applications. Finally, we conclude by offering our perspective on dendrimer engineering that are expected to overcome current obstacles for advancing nucleic acid therapeutics development.
Efficient and safe delivery of nucleic acids remains a major challenge for clinical translation of gene therapies. Here, we report de novo-designed α-helical peptides that coassemble with lipids and nucleic acids to form core-shell, virus-like nanoparticles (VLNs). The peptides combine a cationic N-terminus for nucleic acid binding, an anionic C-terminus for lipid coordination, and pH-responsive residues that promote endolysosomal escape. The resulting VLNs achieved up to 91.2% mRNA transfection and 93.1% siRNA-mediated gene knockdown in vitro, outperforming Lipofectamine 2000. This work demonstrates a programmable, rational design strategy to produce virus-mimetic nanocarriers that address key extracellular and intracellular barriers in nucleic acid therapeutics.
Formalin-fixed paraffin-embedded (FFPE) tissue is the principal substrate for cancer genomic profiling, yet pre-analytical factors affect nucleic acid quality. In our workflow, transurethral resection (TUR) specimens of bladder urothelial carcinoma are fixed promptly but exposed to electrocautery, whereas robot-assisted radical cystectomy specimens are refrigerated overnight before fixation; we compared nucleic acid quality between these specimen types. We analyzed 56 FFPE primary bladder urothelial carcinoma specimens (33 TUR, 23 cystectomy). DNA quality was assessed by the DNA Integrity Number (DIN) and short-to-long cycle threshold ratio (S/L Ct ratio), and RNA quality by the RNA Integrity Number (RIN) and percentage of RNA fragments ≥200 nucleotides (DV200), with group comparisons, Spearman correlations, and multivariable regression (specimen type, fixation duration, storage time). The median DIN (4.4 vs. 3.8, p = 0.004) and S/L Ct ratio (0.943 vs. 0.894, p < 0.001) were higher in TUR than cystectomy specimens; the RIN was also higher (1.9 vs. 1.7, p = 0.040), though low in both groups, and DV200 did not differ (50.3% vs. 47.7%, p = 0.934). In multivariable analysis, TUR specimen type independently predicted higher DIN (β = +0.460, p = 0.040) and S/L Ct ratio (β = +0.442, p = 0.009), whereas longer storage time independently decreased the S/L Ct ratio (β = -0.513, p < 0.001) and RIN (β = -0.352, p = 0.010). In our institutional workflow, TUR specimens showed higher DNA quality metrics than robot-assisted radical cystectomy specimens subjected to overnight refrigerated pre-fixation delay, whereas this workflow-associated advantage did not clearly extend to DV200-defined RNA fragment-length quality. Storage time was associated with selected aspects of nucleic acid deterioration.
Cervical cancer pharmacotherapy is significantly limited by physiological and cellular barriers that restrict drug access to therapeutic targets, resulting in suboptimal biodistribution, systemic toxicity, and the emergence of drug resistance. This review provides a mechanistic and biopharmaceutics-centered analysis of how advanced drug delivery systems are being engineered to overcome these limitations. We critically examine the role of nanocarriers, including lipid-based vesicles, polymeric nanoparticles, and inorganic hybrid systems, in modulating absorption, distribution, and tumor-targeting efficiency, with emphasis on their physicochemical properties and interaction with biological barriers such as the tumor microenvironment and cellular uptake pathways. In parallel, we analyze nucleic acid-based therapeutics (CRISPR/Cas systems, miRNA, and antisense oligonucleotides) from a pharmaceutical sciences perspective, focusing on delivery constraints, stability, intracellular trafficking, and their ability to modulate pharmacological response and drug resistance mechanisms. The review also discusses the integration of immunomodulatory strategies within nanodelivery platforms as a means to alter disease-related biological barriers and improve therapeutic index. Finally, we explore the emerging role of AI-assisted models in optimizing formulation design, predicting pharmacokinetic behavior, and supporting precision dosing strategies in drug development workflows. By integrating drug delivery engineering, molecular biopharmaceutics, and computational optimization, this work outlines a translational framework for overcoming key barriers in pharmaceutical intervention design for oncology applications.
Efficient delivery of nucleic acid therapeutics by lipid nanoparticles (LNPs) depends on complex interaction between vectors and targets. Here, we propose a model wherein LNP tropism is orchestrated synergistically by the particle's surface charge and the target cell's endo/lysosomal vacuolar H+-ATPase (V-ATPase) activity. In vitro, neutral LNPs transfected Fed cells (cells in +FBS medium) with optimal V-ATPase activity more efficiently than -FBS cells, while positively-charged LNPs transfected -FBS cells (cells in -FBS medium) with reduced V-ATPase activity more efficiently than Fed cells. In vivo, this synergy was applicable to liver, versus lung tropism of neutral versus positively-charged LNPs respectively. In addition, pre-condition of the reticuloendothelial system (RES) with empty LNPs enhanced functional delivery to lung but not liver mediated by positively-charged LNPs. Pharmacological inhibition of V-ATPase activity reduced in vitro and in vivo delivery mediated by neutral LNPs. On the other hand, elevating V-ATPase activity via genetic knockdown of ATP6-V1H enhanced in vitro delivery mediated by negatively-charged LNPs. Moreover, we found that the major components of protein corona adsorbed to in vivo neutral LNPs and positively-charged LNPs were shared by each other, except that the latter contained higher levels of coagulation factors and hemoglobins. In summary, our findings uncover a synergistic interaction between LNPs and targets in vitro and in vivo orchestrated by surface charge of LNP and V-ATPase activity of target.
Dry eye disease (DED) is a prevalent disorder affecting millions worldwide, fueled by both the aging population and extensive use of electronic devices. Yet, current treatments for moderate-to-severe DED fail to fully meet the clinical needs due to the lack of effective therapeutics and delivery systems for topical application. Based on the concept of "Barrier to Target," an siRNA-embedded nucleic acid hydrogel modified with a mucin-1 (MUC1) aptamer is developed to actively target the ocular surface for DED treatment. Upon distillation, the adhesive feature and aptamer-mucin recognition of the hydrogel enhance its retention on the ocular surface. Over time, tear dilution and the shear force of blinking lead the hydrogel to degrade into nanosized gel particles, facilitating drug uptake by corneal cells. Subsequently, the embedded siRNA targeting the nuclear factor of kappa-B inhibitor, zeta (NFKBIZ) gene can effectively silence the target gene expression, initiating a cascade of inflammation-related gene suppression. This comprehensive gene regulation effectively reshapes the inflammatory corneal environment to a normal state and alleviates the severity of DED in a mouse model. With the sequence-dependent nature of siRNA drugs, our targeting hydrogel may serve as a general platform for treating various ocular surface diseases.
Cancer care is increasingly driven by molecular classification, yet many key oncogenic drivers remain undruggable, and intrinsic or acquired resistance to treatment frequently limits durable clinical benefit. CRISPR-Cas technologies provide a modular, programmable platform to interrogate and directly manipulate cancer biology via sequence-specific targeting of DNA or RNA and have advanced from experimental tools to the early stages of clinical translation. In this Review, we outline how CRISPR-enabled functional genomics approaches can reveal unexpected cancer dependencies and resistance mechanisms. We discuss emerging applications of CRISPR-based diagnostics in oncology that convert precise nucleic acid sequence recognition into rapid mutation detection. We also discuss applications of CRISPR in therapeutic strategies ranging from ex vivo immune cell engineering to nascent in vivo interventions that directly target tumour-related sequences such as fusion junctions or single-nucleotide variants. Finally, we highlight technological and regulatory challenges, including effective delivery of the editing machinery to cells in vivo, safety and platform-level regulatory frameworks, that will determine the clinical utility of CRISPR-based diagnostics and therapies in oncology.
Infectious diseases are traditionally managed using medicinal herbs in traditional Chinese medicine, Ayurveda and Unani. These conventional therapies are an essential source of new anti-infective drugs considering antimicrobial resistance threatens global public health. The present review critically appraises the use of medicinal plants against bacterial, viral, fungal and parasitic infections in combination with medicinal chemistry and ethnopharmacology. A comprehensive review of ethnobotanical data, phytochemistry and pharmacological studies was performed on the basis of WHO classification of infectious diseases in order to identify repeating medicinal plants and their active ingredients. Over 150 medicinal plants have been discovered by major ethnomedical systems in the course of history and have been used as the remedy of infectious diseases. Essential phytochemicals such as alkaloids, terpenoids, flavonoids, phenolics and saponins showed broad-spectrum anti-infective activity via mechanisms including membrane damage, enzyme inhibition, oxidative stress regulation and interference with nucleic acid synthesis. Some examples of such successful combination of ethnopharmacology with pharmacology include artemisinin, berberine, andrographolide and glycyrrhizin. Nevertheless, the lack of standardization, poor bioavailability and insufficient clinical trials are still problematic.
Reversible genetic medicines are emerging as controllable alternatives to permanent genome editing by enabling programmable modulation of RNA sequence, transcript abundance, chromatin state, and gene expression without irreversible genomic alteration. However, reversibility is not a single binary property: transient editor exposure, decay of the molecular effect, recovery of cellular function, and clinical capacity to stop, redose, or counteract treatment may diverge. This review therefore distinguishes mechanistic, functional, and clinical reversibility while examining targeted delivery systems for RNA-editing and epigenome-editing therapeutics. Key payloads include ADAR-recruiting oligonucleotides, CRISPR-Cas13 RNA editors, guide RNAs, chemically modified RNAs, editor-encoding mRNAs, dCas9 transcriptional regulators, DNA methylation editors, histone-modifying systems, and CRISPRoff-like platforms. We evaluate extracellular and intracellular delivery barriers, including nuclease degradation, immune recognition, renal clearance, liver uptake, cellular entry, endosomal escape, cytoplasmic release, nuclear localization, chromatin access, editing-window duration, off-target activity, immunogenicity, repeat-dosing feasibility, manufacturing, quality control, potency assays, and regulatory translation. Overall, delivery systems for reversible genetic medicines should be judged by tissue selectivity, functional editing, duration of action, reversibility after treatment withdrawal, safety, manufacturability, and clinical controllability.
Atherosclerosis (AS) is a complex cardiovascular disease driven by the interplay of dysregulated lipid metabolism, chronic inflammation, and immune dysfunction. Increasing evidence has revealed that the gut microbiota not only regulates host metabolic homeostasis but also actively contributes to the initiation and progression of AS through intricate interactions with the innate immune system. Microbial-derived signaling molecules, including lipopolysaccharides, outer membrane vesicles, extracellular nucleic acids, and TMAO, can activate Toll-like receptors, the NLRP3 inflammasome, and nucleic acid-sensing pathways, thereby promoting inflammatory cytokine production, endothelial dysfunction, and foam cell formation. In contrast, beneficial microbial metabolites such as short-chain fatty acids, bile acids, and tryptophan-derived metabolites exert immunomodulatory and vasculoprotective effects through signaling pathways involving FFAR2/3, the AhR, the FXR, and TGR5. Conversely, the innate immune system shapes microbial composition and function through barrier defense, phagocytic clearance, and antimicrobial factor production, establishing a dynamic and reciprocal microbiota-immune interaction network. This review systematically summarizes alterations in microbial ecology and innate immune homeostasis associated with atherosclerosis, elucidates the key molecular mechanisms underlying microbiota-innate immune crosstalk, and examines its dynamic involvement across four critical stages of disease evolution: endothelial dysfunction, foam cell formation, plaque progression, and plaque destabilization and rupture. In addition, emerging therapeutic approaches, including microbiota remodeling, modulation of microbial metabolic pathways, and precision microbiome-based interventions, are comprehensively discussed. The microbiota-innate immune axis provides a novel conceptual framework for understanding atherosclerosis pathogenesis and represents a promising target for future disease prevention, risk stratification, and precision therapeutics.
To summarize the research progress on immune microenvironment imbalance and targeted interventions in osteoarthritis comorbid with diabetes mellitus, so as to provide a reference for the development of disease-modifying therapies and individualized local drug-delivery strategies for this comorbid population. Relevant domestic and international studies published in recent years were reviewed. Focusing on the "oxidative stress-immune interaction" axis, the major alterations and cellular network characteristics of the immune microenvironment in osteoarthritis comorbid with diabetes mellitus were summarized, with emphasis on microenvironment-targeted intervention strategies, including small-molecule drug repurposing, nanodelivery systems, exosome/nucleic acid-based therapeutics, and injectable biomaterials. Challenges and prospects related to stratified diagnosis and treatment, efficacy endpoints, and long-term safety in clinical translation were also discussed. The core pathological basis of osteoarthritis comorbid with diabetes mellitus involves hyperglycemia-induced oxidative stress and immunometabolic reprogramming. Through mechanisms such as the accumulation of advanced glycation end products, lipotoxicity, mitochondrial dysfunction, and abnormalities in the gut-joint axis, these changes promote persistent synovitis, extracellular matrix degradation, pain sensitization, and structural joint damage. Immune microenvironment imbalance is mainly characterized by pro-inflammatory polarization of synovial macrophages with impaired efferocytosis, T helper 17 cells/regulatory T cells imbalance, reduced immunomodulatory capacity of mesenchymal stem cells and their exosomes, and senescence-associated immune remodeling in bone marrow lesion areas. Based on these mechanisms, targeted intervention strategies, including small-molecule drug repurposing, nanodelivery systems, exosome/nucleic acid-based therapeutics, and injectable biomaterials, have shown promising application prospects. However, their clinical translation still faces challenges, such as insufficient stratified diagnosis and treatment, inadequate efficacy evaluation systems, and limited long-term safety evidence. The development and progression of osteoarthritis comorbid with diabetes mellitus are closely associated with the persistent interplay among metabolic abnormalities, oxidative stress, and immune microenvironment imbalance. Targeted interventions based on modulation of the local joint microenvironment may relieve pain, improve joint function, and delay the progression of structural joint damage, thereby providing new insights into disease-modifying therapy. Future studies should further refine stratified diagnostic and therapeutic strategies, optimize biomarker selection and delivery platform design, and strengthen long-term safety evaluation to facilitate clinical translation of these strategies. 总结糖尿病共病背景下骨关节炎免疫微环境失衡及靶向干预研究进展，以期为共病人群疾病修饰治疗和个体化局部给药方案的开发提供参考。. 回顾近年国内外相关研究文献，以“氧化应激-免疫互作”为主线，总结糖尿病共病背景下骨关节炎免疫微环境的主要改变和细胞网络特征，重点归纳小分子药物再利用、纳米递送、外泌体/核酸药物和可注射生物材料等微环境靶向干预策略，讨论临床转化中分层诊疗、疗效终点和长期安全性等挑战和前景。. 糖尿病共病骨关节炎的核心病理基础为高血糖诱导的氧化应激与免疫代谢重编程，可通过晚期糖基化终末产物积累、脂毒性、线粒体功能障碍及肠-关节轴异常等机制，促进滑膜炎持续存在、软骨基质降解、疼痛敏化及关节结构损伤。其免疫微环境失衡主要涉及滑膜巨噬细胞促炎偏移与凋亡细胞清除受损、辅助性T细胞17/调节性T细胞失衡、MSCs及其外泌体免疫调节能力减弱，以及骨髓病灶区衰老相关免疫重塑。围绕上述机制，小分子药物再利用、纳米递送、外泌体/核酸药物及可注射生物材料等靶向干预策略显示出一定应用前景，但仍需解决分层诊疗、疗效评价及长期安全性等转化问题。. 糖尿病共病骨关节炎的发生发展与代谢异常、氧化应激和免疫微环境失衡的持续互作密切相关。基于关节局部微环境调控的靶向干预有望缓解疼痛、改善关节功能，并延缓关节结构损伤进展，为疾病修饰治疗提供新思路。未来需进一步完善分层诊疗策略，优化生物标志物筛选与递送平台设计，并加强长期安全性评价，为相关策略的临床转化奠定基础。.
Lipid nanoparticles (LNPs) have emerged as the leading delivery platform for RNA therapeutics, yet the relationship between their internal structure and biological function remains incompletely understood. Cryogenic electron microscopy (cryo-EM) has revealed a striking diversity of LNP morphologies, but a coherent framework linking structural class to formation mechanism and functional outcome has been lacking. Here, based on cryo-EM evidence, we present a systematic classification of LNP morphologies into monophasic (solid-core, multilamellar, and inverse hexagonal) and biphasic (bleb and liposomal) architectures. For each class, we dissect the mechanistic origins of assembly, explaining how ionizable lipid chemistry, helper lipid geometry, RNA cargo properties, and formulation parameters collectively determine structural outcome, and map the spatial distribution of lipid and nucleic acid components within individual particles. We then evaluate how these structural features affect biological fate, from endosomal membrane fusion and cargo release to protein corona formation and in vivo biodistribution. A central finding across the literature is that equivalent morphology does not always guarantee equivalent biological outcome; the pathway by which a given structure is formed critically shapes its intraparticle molecular organization and, consequently, its transfection efficacy. We further discuss how biological environments, particularly endosomal acidification and protein adsorption, dynamically remodel LNP structure and function. By synthesizing structural, mechanistic, and functional insights, this Review aims to establish the design principles needed to rationally engineer LNP morphology for next-generation RNA therapeutics.
Transcription factors (TFs) occupy a central position in cancer biology, functioning as master regulators that translate genetic, epigenetic and environmental cues into cell fate decisions, proliferation, survival, and therapy response. Historically deemed "undruggable" owing to their lack of catalytic sites, conformational flexibility, and engagement in broad protein-DNA and protein-protein interfaces, TFs were long considered beyond the reach of conventional pharmacology. Over the past decades, advances in structural biology, chemical biology, epigenetics, and nucleic acid therapeutics have begun to overcome these challenges, revealing actionable vulnerabilities within TF networks. This review synthesizes current understanding of TF function in tumorigenesis, moving from mechanistic insights at the level of individual TFs to the higher-order organization of transcriptional regulatory networks. It further assesses emerging therapeutic strategies aimed at perturbing aberrant TF activity, encompassing direct inhibition, targeted protein degradation, modulation of TF-cofactor interactions, and nucleic acid-based interventions. We further highlight exemplary TFs and their typical targeting strategies, including Myelocytomatosis oncogene (MYC), Signal transducer and activator of transcription 3 (STAT3), Catenin beta-1 (β-catenin), Yes-associated protein/Transcriptional coactivator with PDZ-binding motif/Transcriptional enhanced associate domain (YAP/TAZ/TEAD), Estrogen receptor/Androgen receptor (ER/AR), and Phosphatase and tensin homolog/Protein kinase B/Forkhead box O (PTEN/AKT/FOXO), which illustrating mechanistic understanding of transcriptional regulation drives therapeutic development and enables genomics-guided precision oncology. By unifying mechanistic insight with pharmacological innovation, we aim to provide a conceptual framework for targeting the transcriptional architecture of cancer and charting paths toward next-generation transcription-directed therapies.
Targeted cancer therapies increasingly require platforms that can penetrate poorly perfused tumor regions while minimizing systemic toxicity. Bacteria, owing to their intrinsic tumor tropism, genetic programmability, and immunostimulatory properties, have re-emerged as versatile anticancer agents, ranging from attenuated tumor-colonizing strains to highly engineered "living therapeutics." In this review, we synthesize the mechanistic foundations and therapeutic advances of bacterial-based cancer therapy through four major themes. First, we examine foundational mechanisms, including tumor-selective colonization, direct oncolysis and cytotoxicity, activation of innate and adaptive immunity, and remodeling of the tumor microenvironment. Second, we discuss engineering strategies that enable controllable delivery of therapeutic payloads, such as cytokines, antibodies and nanobodies, enzyme-prodrug systems, toxins, and nucleic-acid therapeutics, while also improving biosafety and biocontainment. Third, we evaluate combination strategies integrating bacteria with chemotherapy, radiotherapy, phototherapy, and immunotherapy, with emphasis on how bacteria complement conventional modalities by targeting hypoxic, necrotic, and immunologically refractory tumor niches. Fourth, we summarize translational progress, including representative early-phase clinical experiences, manufacturing challenges, and major safety constraints. We also highlight emerging microbiome-disease databases and computational resources that may support target selection, biomarker discovery, and therapy-response stratification. Current evidence supports bacteria as a promising precision modality, particularly for immunologically "cold" or hypoxic tumors; however, major challenges remain in the predictability of intratumoral distribution, host clearance, genetic stability, and long-term safety. Addressing these barriers through rigorous engineering, standardized manufacturing, and clinically meaningful endpoints will be essential for the next generation of bacterial therapeutics in oncology.
Biomacromolecular therapeutics, including proteins and nucleic acids, offer high specificity but face major delivery challenges of stability, cellular uptake, and intracellular trafficking. Synthetic bioinspired strategies, ranging from systems that borrow broad principles from nature to biomimetic carriers that closely imitate biological mechanisms, are increasingly being explored to overcome these barriers. This review examines lipid- and polymer-based systems for protein and nucleic-acid delivery, drawn from two paradigms: virus-mimicking systems and peptide/protein pathway-based mimicry. Virus-mimicking platforms are divided into two groups: structural mimicry (capsid-like nanoparticles, fusogenic liposomes, dendrimers) and functional mimicry (pH-responsive endosomolytic and environmentally triggered systems). Pathway-based approaches span receptor-mediated blood-brain barrier transport, fibrinogen bridging for thrombus targeting, and charge-mediated membrane penetration. Relevant literature was identified through PubMed, Nature, Scopus and Web of Science, focusing on the last 15 years of innovation. Unlike reviews centered on membrane-coated biomimetic carriers or on a single modality or barrier, it uses the cell-membrane interaction as a unifying organizing principle across delivery of both cargo types. Computational design, machine-learning-guided optimization and hybrid lipid-polymer architectures are expected to accelerate translation, while stimuli-responsive, multifunctional nanoparticles integrating targeting, controlled release and diagnostics will likely define the next generation of precision biomacromolecule delivery systems.
Liposomal nanoparticulate drug delivery systems (LNDDSs) are clinically validated nanomedicine platforms seeing regular use in oncology and infectious disease. Their applications have rapidly expanded with several tissue targeting formulations in early-phase clinical trials. Beyond small molecular drugs, LNDDSs are increasingly employed for delivery of nucleic acid therapeutics, such as ribonucleic acid (RNA) based vaccines and immunomodulators. Recent advances in nanomaterials have enabled LNDDSs not only to transport therapeutic agents across systemic biological barriers but also to selectively destabilize plasma and organelle membranes, such as endosomes and mitochondria, addressing a wide range of diseases. This review systematically examines design strategies for LNDDSs that traverse key biological barriers focusing on the blood-tumor barrier, blood-brain barrier, and lymphatic transport barriers. We further explore approaches including fusogenic, pH-, redox- and, enzyme-sensitive and externally (ultrasound and thermal) triggered LNDDSs to facilitate internalization and membrane destabilization for specific organelle-targeting. The mechanisms and representative formulations and of membrane interactions, and clinical progress are discussed. Finally, the translational opportunities and challenges, and future perspectives for rational design of next-generation LNDDSs are addressed.